Aminopyridine derivatives as tam family kinase inhibitors

ABSTRACT

Provided herein are aminopyridine derivatives and pharmaceutical compositions that are useful as TAM family kinase inhibitors.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. §119(e) of U.S.Provisional Patent Application No. 61/909,828 filed Nov. 27, 2013, andU.S. Provisional Patent Application No. 61/909,830 filed Nov. 27, 2013,which applications are incorporated herein by reference in thierentirety.

BACKGROUND

Technical Field

The present disclosure provides compounds that inhibit protein kinasesTyro3, Axl and Mer (TAM family kinases), prodrugs of the compounds,intermediates and methods of synthesizing the compounds and/or prodrugs,pharmaceutical compositions comprising the compounds and/or prodrugs andmethods of using the compounds and/or prodrugs in a variety of contexts,including, for example, in the treatment and/or prevention of variousdiseases that are responsive to TAM family kinase inhibition and/or thatare mediated, at least in part, by abnormal TAM family kinase activity.

Description of the Related Art

The receptor tyrosine kinases (RTKs) are transmembrane proteins andfunction as sensors for extracellular ligands, which transduce signalsfrom extracellular medium to the cytoplasm. Their activation leads tothe recruitment, phosphorylation, and activation of the downstreamsignaling pathways, which ultimately regulate cellular functions such asproliferation, growth, differentiation or motility. Abnormaloverexpression levels and/or enhanced activities of RTKs have beenassociated to a variety of human cancers, leading to a strong interestin the development of inhibitors against these human cancers. Tyro-3,Axl, and Mer constitute the TAM family of RTKs characterized by aconserved sequence within the kinase domain and adhesion molecule likeextracellular domains. With varying degree of specificity and affinity,TAM kinases can be activated by the vitamin K-dependent ligand Gas6and/or Protein S. Strong evidence supports their association with bothcancer (gain-in-function) and autoimmunity (loss-of-function). TAMkinase signaling has been implicated in a myriad of cellular responses,many of which are the hallmarks of cancer, including proliferation,survival, migration, invasion and angiogenesis. In addition, TAM playspivotal roles innate immunity through inhibiting inflammation inmacrophages and dendritic cells and promoting the phagocytosis ofapoptotic cells. While the oncogenic activity of TAM kinases appears tobe mediated via PI3K/AKT pathway, the JAK-STAT pathway is critical fortheir roles in immune responses. Overexpression of TAM kinases has beenobserved in over 20 human cancers. The level of their expression wasshown to correlate with shorter progression-free and overall survivaland their up-regulation has been linked to cancer resistance tocytotoxic drugs and targeted therapies.

While broadly expressed in various human tumor cell lines, Tyro3, Axl,and Mer exhibit their respective tissue-specific expression patterns.Tyro-3 is highly expressed in the nervous system whereas, Axl isexpressed ubiquitously. Higher level of Mer is often found inhematopoietic lineages such as monocytes/macrophages, dendritic cells,NK cells, NKT cells, megakaryocytes, and platelets.

Compared to Axl and Mer, Tyro3 is the least studied kinase of the TAMfamily. Implication of Tyro3 in tumorigenesis was only recentlysubstantiated by recent studies, which revealed Tyro3 is a potentialoncogene in melanoma that is linked to poorer outcome of patientssuffering from melanoma regardless the BRAF or NRAS status by conferringsurvival advantage to melanoma cells. It was also identified as one ofkinases significantly up-regulated in lung cancer by a phosphoproteomicscreen. High level of Tyro3 expression has also been correlated withthyroid cancer.

As the founding member of the TAM kinase family, Axl was discovered as atransforming gene in chronic myelogenous leukemia (CML). Axloverexpression has since been reported in a wide range of humanmalignancies and is associated with invasiveness and metastasis in lung,prostate, breast and pancreatic cancer. Axl is also an importantregulator of breast cancer metastasis and EMT. Activation of the Axlkinase confers resistance to EGFR targeted therapy in lung cancer.Upregulation of Axl has been implicated as a mechanism of resistance toimatinib in CML and gastrointestinal stromal tumors and to lapatinib inbreast cancer. Axl expression has also been associated withchemoresistance in AML, NSCLC and ovarian cancer. Mer isoverexpressed/over-activated in a wide variety of cancers and has beenestablished as a therapeutic target in hematopoietic malignancies andsolid tumors including leukemia, nonsmall cell lung cancer,glioblastoma, melanoma, prostate cancer, breast cancer, colon cancer,gastric cancer, pituitary adenomas, and rhabdomyosarcomas. Oncogenicpotential of Mer is mediated through the activation of several canonicaloncogenic signaling pathways including the mitogen-activated proteinkinase and phosphoinositide 3-kinase pathways, as well as regulation ofsignal transducer and activator of transcription family members,migration-associated proteins including the focal adhesion kinase andmyosin light chain 2, and prosurvival proteins such as survivin andBcl-2. In neoplastic cells, these signaling events result in functionalphenotypes such as decreased apoptosis, increased migration,chemoresistance, increased colony formation, and increased tumorformation in murine models. Conversely, Mer inhibition by genetic orpharmacologic means can reverse these pro-oncogenic phenotypes.

To date, the following literature reports described small moleculeinhibitors of Tyro3, Axl and/or Mer: Zhang et al., J. Med. Chem., 2014,57, 7031-7041; Rho et al., Cancer Res., 2014, 74, 253-262; Traore etal., Euro. J. Med. Chem., 2013, 70, 789-801; Zhang et al., J. Med.Chem., 2013, 56, 9683-9692; Zhang et al., J. Med. Chem., 2013, 56,9693-9700; Liu et al., Euro. J. Med. Chem., 2013, 65, 83-93; Powell etal., Bioorg. Med. Chem. Lett., 2013, 23, 1051-1055; Powell et al.,Bioorg. Med. Chem. Lett., 2013, 23, 1046-1050; Suarez et al., Euro. J.Med. Chem., 2013, 61, 2-25; M. F. Burbridge et al., Mol. Cancer Ther.,2013, 12, 1749-1762; Powell et al., Bioorg. Med. Chem. Lett. 2012, 22,190-193; Liu et al., ACS Med. Chem. Lett., 2012, 3, 129-134; Mollard etal., ACS Med. Chem. Lett., 2011, 2, 907-912; Holland et al., CancerRes., 2010, 70(4), 1544-1554.; Ono et al., poster number MEDI-393,244^(th) ACS National Meeting & Exposition, Philadelphia, Pa., Aug.19-23, 2012; Zhang et al., poster number MEDI-56, 244^(th) ACS NationalMeeting & Exposition, Philadelphia, Pa., Aug. 19-23, 2012; Yang et al.,poster number MEDI-265, 242^(nd) ACS National Meeting & Exposition,Denver, Colo., Aug. 28-Sep. 1, 2011; Zhang et al., poster numberMEDI-62, 242^(nd) ACS National Meeting & Exposition, Denver, Colo., Aug.28-Sep. 1, 2011; Wang et al., poster number MEDI-18, 242^(nd) ACSNational Meeting & Exposition, Denver, Colo., Aug. 28-Sep. 1, 2011;Huang et al., J. Stru. Biol. 2009, 165, 88-96. Axl inhibitors have alsobeen disclosed in US2008188455A1; WO2007030680A2; WO2008045978A1;WO2008080134A2; WO2008083353A1; WO2008083354A1; WO2008083356A1;WO2008083357A1; WO2008083367A2; WO2008128072A2; WO2009007390A2;WO2009024825A1; WO2009047514A1; WO2009053737A2; WO2009054864A1;WO2009127417A1; WO2010005876A2; WO2010005879A1; WO2010083465A1;WO2010090764A1; WO2011045084A1; WO2011138751A2; WO2012028332A1;WO2012135800A1; WO2013074633A1; WO2013115280A1; WO2013162061A1.

SUMMARY

The present disclosure provides 2-aminopyridine derivatives that arecapable of inhibiting the activity of TAM family kinases. Methods ofusing such derivatives to inhibit the activity of TAM family kinases andpharmaceutical compositions comprising such derivatives are alsodisclosed.

One embodiment provides compounds of formula (I):

wherein:

W is

each A, A¹ and A² is the same or different and independently —N═, —CR⁵═,or —O—;

L is heteroaryl, heterocyclyl, —N(R⁶)—, —O—, —C(O)—, —C(O)O—, —S(O)_(t)—where t is 0, 1, or 2, —CON(R⁶)—, —N(R⁶)CO—, —SO₂N(R⁶)—, or—N(R⁶)CON(R⁶)—, provided that when L is heteroaryl, L is not pyridinyl,pyrazinyl or thienyl;

R¹ is alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R² is hydrogen, heterocyclyl, heterocyclylalkyl, cycloalkyl, alkyl,aralkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, or aryl;

each R³ and R⁴ is the same or different and independently hydrogen,alkyl, aralkyl, alkenyl, aralkenyl, alkynyl, aralkynyl, cycloalkyl,cycloalkylalkyl, halo, or haloalkyl;

R⁵, at each occurrence, is hydrogen, alkyl, aralkyl, cycloalkyl,cycloalkylalkyl, halo, or haloalkyl;

R⁶ is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, or haloalkyl,

a stereoisomer, enantiomer or tautomer thereof, an isotopically enrichedderivative thereof, a pharmaceutically acceptable salt thereof, apharmaceutical composition thereof or a prodrug thereof.

Of the compounds of Formula (I), an embodiment provides compound ofFormula (IA):

wherein,

A, A¹, A², R¹, R³, and R⁴ are as defined above.

Of the compounds of Formula (IA), an embodiment provides compounds ofFormula (IA1):

wherein:

R¹, R², R³, and R⁴ are as defined above.

Of the compounds of Formula (IA), another embodiment provides compoundsof Formula (IA2):

wherein, R¹, R², R³, and R⁴ are as defined above.

Of the compounds of Formula (IA), another embodiment provides compoundsof Formula (IA3):

wherein, R¹, R², R³, and R⁴ are as defined above.

Of the compounds of Formula (IA), another embodiment provides compoundsof Formula (IA4):

wherein, R¹, R², R³, and R⁴ are as defined above.

Of the compounds of Formula (IA), another embodiment provides compoundsof Formula (IA5):

wherein, R¹, R², R³, and R⁴ are as defined above.

Of the compounds of Formula (IA), another embodiment provides compoundsof Formula (IA6):

wherein, R¹, R², R³, and R⁴ are as defined above.

Of the compounds of Formula (IA), another embodiment provides compoundsof Formula (IA7):

wherein, R¹, R², R³, and R⁴ are as defined above.

Of the compounds of Formula (I), an embodiment provides compound ofFormula (IB):

wherein,

A, A¹, A², R¹, R³, R⁴, and R⁵ are as defined above,

L is heteroaryl or heterocycle;

R⁷ is hydrogen, alkyl, alkoxy, or halo;

X is —O—, —NR⁸—, or —C(R⁹)₂—;

R⁸ is hydrogen, alkyl, or —C(O)R¹⁰—;

each R⁹ is independently hydrogen, alkyl, alkoxy, or halo; and

R¹⁰ is alkyl, cycloalkyl, aryl, alkoxy, or aralkyl.

Of the compounds of Formula (IB), an embodiment provides compound ofFormula (IB1):

wherein,

A, A¹, A², R¹, R³, R⁴, R⁷, and R⁸ are as defined above.

Of the compounds of Formula (IB), an embodiment provides compound ofFormula (IB2):

wherein,

A, A¹, A², R¹, R³, R⁴, and R⁷ are as defined above.

Of the compounds of Formula (IB), an embodiment provides compound ofFormula (IB3):

wherein,

A, A¹, A², R¹, R³, R⁴, R⁷, and R⁹ are as defined above.

Yet another embodiment provides a pharmaceutical composition of acompound of any one of Formula (I), (IA), or (IB), or any one of thesubstructures as represented by Formula (IA1), (IA2), (IA3), (IA4),(IA5), (IA6), (IA7), (IB1), (IB2), or (IB3), or any one the specificcompounds disclosed herein.

Yet another embodiment provides a method of treating leukemia andlymphoma comprising administering to a subject in need thereof apharmaceutically effective amount of a compound of Formula (I), (IA), or(IB), or any one of the substructures as represented by Formula (IA1),(IA2), (IA3), (IA4), (IA5), (IA6), (IA7), (IB1), (IB2), or (IB3)or apharmaceutical composition comprising the same.

Yet another embodiment provides a method of treating endometriosiscomprising administering to a subject in need thereof a pharmaceuticallyeffective amount of a compound of a compound of Formula (I), (IA), or(IB), or any one of the substructures as represented by Formula (IA1),(IA2), (IA3), (IA4), (IA5), (IA6), (IA7), (IB1), (IB2), or (IB3) or apharmaceutical composition comprising the same.

Yet another embodiment provides a method of treating restenosiscomprising administering to a subject in need thereof a pharmaceuticallyeffective amount of a compound of a compound of Formula (I), (IA), or(IB), or any one of the substructures as represented by Formula (IA1),(IA2), (IA3), (IA4), (IA5), (IA6), (IA7), (IB1), (IB2), or (IB3) or apharmaceutical composition comprising the same.

Yet another embodiment provides a method of treatingatherosclerosis/thrombosis comprising administering to a subject in needthereof a pharmaceutically effective amount of a compound of a compoundof Formula (I), (IA), or (IB), or any one of the substructures asrepresented by Formula (IA1), (IA2), (IA3), (IA4), (IA5), (IA6), (IA7),(IB1), (IB2), or (IB3) or a pharmaceutical composition comprising thesame.

Yet another embodiment provides a method of treating psoriasiscomprising administering to a subject in need thereof a pharmaceuticallyeffective amount of a compound of Formula (I), (IA), or (IB), or any oneof the substructures as represented by Formula (IA1), (IA2), (IA3),(IA4), (IA5), (IA6), (IA7), (IB1), (IB2), or (IB3) or a pharmaceuticalcomposition comprising the same.

Yet another embodiment provides a method of treating age-related maculardegeneration or diabetic retinopathy comprising administering to asubject in need thereof a pharmaceutically effective amount of acompound of Formula (I), (IA), or (IB), or any one of the substructuresas represented by Formula (IA1), (IA2), (IA3), (IA4), (IA5), (IA6),(IA7), (IB1), (IB2), or (IB3) or a pharmaceutical composition comprisingthe same.

Yet another embodiment provides a method of treating retinopathy ofprematurity comprising administering to a subject in need thereof apharmaceutically effective amount of a compound of Formula (I), (IA), or(IB), or any one of the substructures as represented by Formula (IA1),(IA2), (IA3), (IA4), (IA5), (IA6), (IA7), (IB1), (IB2), or (IB3) or apharmaceutical composition comprising the same.

Yet another embodiment provides a method of treating renal transplantrejection comprising administering to a subject in need thereof apharmaceutically effective amount of a compound of Formula (I), (IA), or(IB), or any one of the substructures as represented by Formula (IA1),(IA2), (IA3), (IA4), (IA5), (IA6), (IA7), (IB1), (IB2), or (IB3) or apharmaceutical composition comprising the same.

Yet another embodiment provides a method of treating rheumatoidarthritis comprising administering to a subject in need thereof apharmaceutically effective amount of a compound of Formula (I), (IA), or(IB), or any one of the substructures as represented by Formula (IA1),(IA2), (IA3), (IA4), (IA5), (IA6), (IA7), (IB1), (IB2), or (IB3) or apharmaceutical composition comprising the same.

Yet another embodiment provides a method of treating osteoarthritiscomprising administering to a subject in need thereof a pharmaceuticallyeffective amount of a compound of a compound of Formula (I), (IA), or(IB), or any one of the substructures as represented by Formula (IA1),(IA2), (IA3), (IA4), (IA5), (IA6), (IA7), (IB1), (IB2), or (IB3) or apharmaceutical composition comprising the same.

Yet another embodiment provides a method of treating osteoporosiscomprising administering to a subject in need thereof a pharmaceuticallyeffective amount of a compound of Formula (I), (IA), or (IB), or any oneof the substructures as represented by Formula (IA1), (IA2), (IA3),(IA4), (IA5), (IA6), (IA7), (IB1), (IB2), or (IB3) or a pharmaceuticalcomposition comprising the same.

Yet another embodiment provides a method of treating cataractscomprising administering to a subject in need thereof a pharmaceuticallyeffective amount of a compound of a compound of Formula (I), (IA), or(IB), or any one of the substructures as represented by Formula (IA1),(IA2), (IA3), (IA4), (IA5), (IA6), (IA7), (IB1), (IB2), or (IB3) or apharmaceutical composition comprising the same.

Yet another embodiment provides a method of preventing/treating tumormetastasis or treating metastasized tumors comprising administering to asubject in need thereof a pharmaceutically effective amount of acompound of a compound of Formula (I), (IA), or (IB), or any one of thesubstructures as represented by Formula (IA1), (IA2), (IA3), (IA4),(IA5), (IA6), (IA7), (IB1), (IB2), or (IB3) or a pharmaceuticalcomposition comprising the same.

DETAILED DESCRIPTION Definitions

Certain chemical groups named herein are preceded by a shorthandnotation indicating the total number of carbon atoms that are to befound in the indicated chemical group. For example; C₇-C₁₂alkyldescribes an alkyl group, as defined below, having a total of 7 to 12carbon atoms, and C₄-C₁₂cycloalkylalkyl describes a cycloalkylalkylgroup, as defined below, having a total of 4 to 12 carbon atoms. Thetotal number of carbons in the shorthand notation does not includecarbons that may exist in substituents of the group described.

Accordingly, as used in the specification and appended claims, unlessspecified to the contrary, the following terms have the meaningindicated:

“Amino” refers to the —NH₂ radical.

“Methoxy” refers to the —OCH₃ radical.

“Cyano” refers to the —CN radical.

“Nitro” refers to the —NO₂ radical.

“Trifluoromethyl” refers to the —CF₃ radical.

“Oxo” refers to the ═O.

“Thioxo” refers to the ═S.

“Acyl” refers to —C(O)R¹⁴ radical, wherein R¹⁴ is hydrogen, alkyl,haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl;

“Alkyl” refers to a straight or branched hydrocarbon chain radical, whenunsubstituted, consisting solely of carbon and hydrogen atoms,containing no unsaturation, having from one to twelve carbon atoms,preferably one to eight carbon atoms or one to six carbon atoms, andwhich is attached to the rest of the molecule by a single bond, e.g.,methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl,1,1-dimethylethyl (t-butyl), and the like. Unless stated otherwisespecifically in the specification, an alkyl group may be optionallysubstituted by one or more substituents, as defined herein. “Alkenyl”refers to a straight or branched hydrocarbon chain radical group, whenunsubstituted, consisting solely of carbon and hydrogen atoms,containing at least one double bond, having from two to twelve carbonatoms, preferably one to eight carbon atoms and which is attached to therest of the molecule by a single bond, e.g., ethenyl, prop-1-enyl,but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless statedotherwise specifically in the specification, an alkenyl group may beoptionally substituted by one of or more substituents, as definedherein.

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalgroup, when unsubstituted, consisting solely of carbon and hydrogenatoms, containing at least one triple bond, optionally containing atleast one double bond, having from two to twelve carbon atoms,preferably one to eight carbon atoms and which is attached to the restof the molecule by a single bond, for example, ethynyl, propynyl,butynyl, pentynyl, hexynyl, and the like. Unless stated otherwisespecifically in the specification, an alkynyl group may be optionallysubstituted by one or more substituents, as defined herein. “Alkylene”and “alkylene chain” refer to a straight or branched divalenthydrocarbon chain, linking the rest of the molecule to a radical group,consisting solely of carbon and hydrogen, containing no unsaturation andhaving from one to twelve carbon atoms, preferably having from one toeight carbons, e.g., methylene, ethylene, propylene, n-butylene, and thelike. The alkylene chain may be attached to the rest of the molecule andto the radical group through one carbon within the chain or through anytwo carbons within the chain.

“Alkenylene” and “alkenylene chain” refer to a straight or brancheddivalent hydrocarbon chain linking the rest of the molecule to a radicalgroup, consisting solely of carbon and hydrogen, containing at least onedouble bond and having from two to twelve carbon atoms, e.g.,ethenylene, propenylene, n-butenylene, and the like. The alkenylenechain is attached to the rest of the molecule through a single bond andto the radical group through a double bond or a single bond. The pointsof attachment of the alkenylene chain to the rest of the molecule and tothe radical group can be through one carbon or any two carbons withinthe chain.

“Alkoxy” refers to a radical of the formula —OR_(a) where R_(a) is analkyl radical as defined above. The alkyl part of the alkoxy radical maybe optionally substituted as defined above for an alkyl radical.

“Aryl” refers to aromatic monocyclic or multi-cyclic hydrocarbon ringsystem, when unsubstituted, consisting only of hydrogen and carbon andcontaining from 6 to 19 carbon atoms, preferably 6 to 10 carbon atoms,where the ring system may be partially or fully saturated. Aryl groupsinclude, but are not limited to groups such as fluorenyl, phenyl andnaphthyl. Unless stated otherwise specifically in the specification, theterm “aryl” or the prefix “ar-” (such as in “aralkyl”) is meant toinclude aryl radicals optionally substituted by one or moresubstituents, as defined herein. “Aralkyl” refers to a radical of theformula —R_(a)R_(b) where R_(a) is an alkyl radical as defined above andR_(b) is one or more aryl radicals as defined above, e.g., benzyl,diphenylmethyl and the like. The aryl part of the aralkyl radical may beoptionally substituted as described above for an aryl group. The alkylpart of the aralkyl radical may be optionally substituted as definedabove for an alkyl group.

“Aralkenyl” refers to a radical of the formula —R_(c)R_(b) where R_(c)is an alkenyl radical as defined above and R_(b) is one or more arylradicals as defined above, which may be optionally substituted asdescribed above. The aryl part of the aralkenyl radical may beoptionally substituted as described above for an aryl group. The alkenylpart of the aralkenyl radical may be optionally substituted as definedabove for an alkenyl group.

“Aralkynyl” refers to a radical of the formula —R_(d)R_(b) where R_(d)is an alkynyl radical as defined above and R_(b) is one or more arylradicals as defined above. The aryl part of the aralkynyl radical may beoptionally substituted as described above for an aryl group. The alkynylpart of the aralkynyl radical may be optionally substituted as definedabove for an alkynyl group.

“Cycloalkyl” refers to a stable non-aromatic monocyclic or bicyclichydrocarbon radical, when unsubstituted, consisting solely of carbon andhydrogen atoms, having from three to fifteen carbon atoms, preferablyhaving from three to twelve carbon atoms, and which is saturated orunsaturated and attached to the rest of the molecule by a single bond,e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decalinyl andthe like. Unless otherwise stated specifically in the specification, theterm “cycloalkyl” is meant to include cycloalkyl radicals which areoptionally substituted by one or more substituents, as defined herein.“Cycloalkylalkyl” refers to a radical of the formula —R_(a)R_(d) whereR_(a) is an alkyl radical as defined above and R_(d) is a cycloalkylradical as defined above. The cycloalkyl part of the cycloalkyl radicalmay be optionally substituted as defined above for a cycloalkyl radical.The alkyl part of the cycloalkyl radical may be optionally substitutedas defined above for an alkyl radical.

“Halo” refers to bromo, chloro, fluoro or iodo.

“Haloalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above. One or morecarbons of the alkyl radical may be substituted by the one or more haloradicals. Examples of haloalkyl include, trifluoromethyl,difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl,1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoro-propyl,1-bromomethyl-2-bromoethyl, and the like. The alkyl part of thehaloalkyl radical may be optionally substituted as defined above for analkyl group.

“Haloalkenyl” refers to an alkenyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,2-bromoethenyl, 3-bromoprop-1-enyl, and the like. The alkenyl part ofthe haloalkenyl radical may be optionally substituted as defined abovefor an alkyl group.

“Heterocyclyl” refers to a stable 3- to 18-membered non-aromatic ringradical including, as ring atoms, at least one carbon atom and from oneto five heteroatoms selected from the group consisting of nitrogen,oxygen and sulfur. For purposes of this disclosure, the heterocyclylradical may be a monocyclic, bicyclic, tricyclic or tetracyclic ringsystem, which may include fused or bridged ring systems; and thenitrogen, carbon or sulfur atoms in the heterocyclyl radical may beoptionally oxidized; and the nitrogen atom may be optionallyquaternized; and the heterocyclyl radical may be partially or fullysaturated. Examples of such heterocyclyl radicals include, but are notlimited to, dioxolanyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, thiazolidinyl,tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl,thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl.Unless stated otherwise specifically in the specification, the term“heterocyclyl” is meant to include heterocyclyl radicals as definedabove which are optionally substituted by one or more substituents, asdefined herein. When the heterocyclyl is a substituent of anothermoiety, the heterocyclyl is monovalent, which means that theheterocyclyl is connected to the other moiety by a single ring atom. Anexample of a monovalent heterocyclyl can be found in the radical ofheterocyclylalkyl, in which a heterocyclyl group is a substituent of analkyl group. When heterocyclyl is a linker moiety (L) of Formula (I),the heterocyclyl is a divalent radical. In this occurrence, theheterocyclyl (as L) is linked, by two of its ring atoms, to the2-aminopyridine moiety and R² of Formula (I). An example of a divalentheterocyclyl is 1,4-piperidinyl, shown below:

“Heterocyclylalkyl” refers to a radical of the formula —R_(a)R_(e) whereR_(a) is an alkyl radical as defined above and R_(e) is a heterocyclylradical as defined above, and if the heterocyclyl is anitrogen-containing heterocyclyl, the heterocyclyl may be attached tothe alkyl radical at the nitrogen atom. The alkyl part of theheterocyclylalkyl radical may be optionally substituted as defined abovefor an alkyl group. The heterocyclyl part of the heterocyclylalkylradical may be optionally substituted as defined above for aheterocyclyl group.

“Heteroaryl” refers to a 5- to 18-membered aromatic ring radicalincluding, as ring atoms, at least one carbon atom and from one to fiveheteroatoms selected from the group consisting of nitrogen, oxygen andsulfur. For purposes of this disclosure, the heteroaryl radical may be amonocyclic, bicyclic, tricyclic or tetracyclic ring system, which mayinclude fused or bridged ring systems; and the nitrogen, carbon orsulfur atoms in the heteroaryl radical may be optionally oxidized; andthe nitrogen atom may be optionally quaternized. Examples include, butare not limited to, azepinyl, acridinyl, benzimidazolyl, benzthiazolyl,benzindolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl,benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl,benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl),benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl,cinnolinyl, dibenzofuranyl, furanyl, furanonyl, isothiazolyl,imidazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl,oxazolyl, oxiranyl, phenazinyl, phenothiazinyl, phenoxazinyl,phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl,pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl,quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl,triazolyl, tetrazolyl, triazinyl, and thiophenyl. Unless statedotherwise specifically in the specification, the term “heteroaryl” ismeant to include heteroaryl radicals as defined above which areoptionally substituted by one or more substituents, as defined herein.Heteroaryl, as defined herein, may be monovalent or divalent. Whenheteroaryl is a substituent of another moiety, the heteroaryl ismonovalent, which means that the heteroaryl is connected to the othermoiety by a single ring atom. An example of a monovalent heteroaryl canbe found in the radical of heteroarylalkyl, in which an alkyl group issubstituted with a heteroaryl group. When heteroaryl is a linker moiety(L) of Formula (I), the heteroaryl is a divalent radical. In thisoccurrence, the heteroaryl (as L) is linked, by two of its ring atoms,to the 2-aminopyridine moiety and R² of Formula (I). An example of adivalent heteroaryl is 1H-pyrazol-4-yl, shown below:

“Heteroarylalkyl” refers to a radical of the formula —R_(a)R_(f) whereR_(a) is an alkyl radical as defined above and R_(f) is a heteroarylradical as defined above. The heteroaryl part of the heteroarylalkylradical may be optionally substituted as defined above for a heteroarylgroup. The alkyl part of the heteroarylalkyl radical may be optionallysubstituted as defined above for an alkyl group.

“Heteroarylalkenyl” refers to a radical of the formula —R_(c)R_(g) whereR_(c) is an alkenyl radical as defined above and R_(g) is a heteroarylradical as defined above. The heteroaryl part of the heteroarylalkenylradical may be optionally substituted as defined above for a heteroarylgroup. The alkenyl part of the heteroarylalkenyl radical may beoptionally substituted as defined above for an alkenyl group.

“N-heteroaryl” is a subset of heteroaryl, and refers to a heteroarylhaving at least one nitrogen ring atom. Heteroaryl is otherwise asdefined as herein. Examples of N-heteroaryls include, withoutlimitation, benzimidazolyl, benzindolyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, imidazolyl,indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, indolizinyl,isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl,pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl,isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, andtriazinyl.

“N-heterocyclyl” is a subset of heterocyclyl, and refers to aheterocyclyl having at least one nitrogen ring atom. Heterocyclyl isotherwise as defined as herein. Examples of N-heterocyclyls include,without limitation, decahydroisoquinolyl, imidazolinyl, imidazolidinyl,isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl,octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl,4-piperidonyl, pyrrolidinyl, pyrazolidinyl, thiazolidinyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl.

“Substituent” refers to a radical (a single non-hydrogen atom or afunctional group) that is or can be bonded to another molecule. Ansubstituent is therefore any one of the following radicals: alkyl,alkenyl, amino, halo, haloalkyl, haloalkenyl, cyano, oxo, thioxo, nitro,aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, heteroarylalkyl, —OR¹⁴, —OC(O)R¹⁴,—N(R¹⁴)₂, —C(O)R¹⁴, —C(O)OR¹⁴, —C(O)N(R¹⁴)₂, —N(R¹⁴)C(O)OR¹⁶,—N(R¹⁴)C(O)R¹⁶, —N(R¹⁴)(S(O)_(t)R¹⁶) (where t is 1 to 2), —S(O)_(t)OR¹⁶(where t is 1 to 2), —S(O)_(t)R¹⁶ (where t is 0 to 2), and—S(O)_(t)N(R¹⁴)₂ (where t is 1 to 2) where each R¹⁴ is independentlyhydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl(optionally substituted with one or more halo groups), aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; and eachR¹⁶ is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, andwhere each of the above substituents is unsubstituted unless otherwiseindicated.

“Prodrugs” refers to a compound that may be converted underphysiological conditions or by solvolysis to a biologically activecompound of Formula (I) or any one of the substructures. Thus, the term“prodrug” refers to a metabolic precursor of a compound of Formula (I)or any one of the substructures, that is pharmaceutically acceptable;the latter is also referred to as a “parent compound.” A prodrug may beinactive when administered to a subject in need thereof, but isconverted in vivo to an active compound, i.e., the parent compound.Prodrugs are typically rapidly transformed in vivo to yield the parentcompound, for example, by hydrolysis in blood. The prodrug compoundoften offers advantages of solubility, tissue compatibility or delayedrelease in a mammalian organism (see, Bundgard, H., Design of Prodrugs(1985), pp. 7-9, 21-24, Elsevier, Amsterdam).

A discussion of prodrugs is provided in Higuchi, T., et al., “Pro-drugsas Novel Delivery Systems,” A.C.S. Symposium Series, Vol. 14, and inBioreversible Carriers in Drug Design, ed. Edward B. Roche, AmericanPharmaceutical Association and Pergamon Press, 1987, both of which areincorporated in full by reference herein.

The term “prodrug” is also meant to include any covalently bondedcarriers which release the active compound of the disclosure in vivowhen such prodrug is administered to a mammalian subject. Prodrugs of acompound of the disclosure may be prepared by modifying functionalgroups present in the compound of Formula (I) or any one of thesubstructures in such a way that the modifications are cleaved, eitherin routine manipulation or in vivo, to the parent compound. Prodrugsinclude compounds of the disclosure wherein a hydroxy, amino or mercaptogroup is bonded to any group that, when the prodrug disclosure isadministered to a mammalian subject, cleaves to restore the freehydroxy, free amino or free mercapto group, respectively. Examples ofprodrugs include, but are not limited to, acetate, formate and benzoate,and phosphate derivatives of alcohol or amine functional groups in thecompounds of Formula (I), (IA), (IB) or any one of the substructures.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

“Mammal” or “mammalian subject” includes humans and domestic animals,such as cats, dogs, swine, cattle, sheep, goats, horses, rabbits, andthe like.

“Optional” or “optionally” means that the subsequently described eventof circumstances may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl radical may or may not be substituted and that the descriptionincludes both substituted aryl radicals and aryl radicals having nosubstitution.

“Pharmaceutically acceptable carrier, diluent or excipient” includeswithout limitation any adjuvant, carrier, excipient, glidant, sweeteningagent, diluent, preservative, dye/colorant, flavor enhancer, surfactant,wetting agent, dispersing agent, suspending agent, stabilizer, isotonicagent, solvent, or emulsifier which has been approved by the UnitedStates Food and Drug Administration as being acceptable for use inhumans or domestic animals.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as, but not limited to,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, and organic acids such as, but not limitedto, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid,ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid,4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid,capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid,citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonicacid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid,fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid,gluconic acid, glucuronic acid, glutamic acid, glutaric acid,2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuricacid, isobutyric acid, lactic acid, lactobionic acid, lauric acid,maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonicacid, mucic acid, naphthalene-1,5-disulfonic acid,naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid,oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid,propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid,4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid,tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroaceticacid, undecylenic acid, and the like.

“Pharmaceutically acceptable base addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Salts derived from inorganic bases include, but are notlimited to, the sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Preferred inorganic salts are the ammonium, sodium, potassium, calcium,and magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as ammonia,isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, diethanolamine, ethanolamine, deanol,2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine,lysine, arginine, histidine, caffeine, procaine, hydrab amine, choline,betaine, benethamine, benzathine, ethylenediamine, glucosamine,methylglucamine, theobromine, triethanolamine, tromethamine, purines,piperazine, piperidine, N-ethylpiperidine, polyamine resins and thelike. Particularly preferred organic bases are isopropylamine,diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, cholineand caffeine.

Often crystallizations produce a solvate of the compound of thedisclosure. As used herein, the term “solvate” refers to an aggregatethat comprises one or more molecules of a compound of the disclosurewith one or more molecules of solvent. The solvent may be water, inwhich case the solvate may be a hydrate. Alternatively, the solvent maybe an organic solvent. Thus, the compounds of the present disclosure mayexist as a hydrate, including a monohydrate, dihydrate, hemihydrate,sesquihydrate, trihydrate, tetrahydrate and the like, as well as thecorresponding solvated forms. The compound of the disclosure may be truesolvates, while in other cases, the compound of the disclosure maymerely retain adventitious water or be a mixture of water plus someadventitious solvent.

A “pharmaceutical composition” refers to a formulation of a compound ofthe disclosure and a medium generally accepted in the art for thedelivery of the biologically active compound to mammals, e.g., humans.Such a medium includes all pharmaceutically acceptable carriers,diluents or excipients therefor.

“Therapeutically effective amount” refers to that amount of a compoundof the disclosure which, when administered to a mammal, preferably ahuman, is sufficient to effect treatment, as defined below, of a diseaseor condition in the mammal, preferably a human. The amount of a compoundof the disclosure which constitutes a “therapeutically effective amount”will vary depending on the compound, the condition and its severity, andthe age of the mammal to be treated, but can be determined routinely byone of ordinary skill in the art having regard to his own knowledge andto this disclosure.

“Treating” or “treatment” as used herein covers the treatment of thedisease or condition of interest in a mammal, preferably a human, havingthe disease or disorder of interest, and includes:

(i) preventing the disease or condition from occurring in a mammal, inparticular, when such mammal is predisposed to the condition but has notyet been diagnosed as having it;

(ii) inhibiting the disease or condition, i.e., arresting itsdevelopment; Or

(iii) relieving the disease or condition, i.e., causing regression ofthe disease or condition.

As used herein, the terms “disease” and “condition” may be usedinterchangeably or may be different in that the particular malady orcondition may not have a known causative agent (so that etiology has notyet been worked out) and it is therefore not yet recognized as a diseasebut only as an undesirable condition or syndrome, wherein a more or lessspecific set of symptoms have been identified by clinicians.

The compounds of the disclosure, or their pharmaceutically acceptablesalts may contain one or more asymmetric centers and may thus give riseto enantiomers, diastereomers, and other stereoisomeric forms that maybe defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as(D)- or (L)- for amino acids. The present disclosure is meant to includeall such possible isomers, as well as their racemic and optically pureforms. Optically active (+) and (−), (R)- and (S)-, or (D)- and(L)-isomers may be prepared using chiral synthons or chiral reagents, orresolved using conventional techniques, such as HPLC using a chiralcolumn. When the compounds described herein contain olefinic doublebonds or other centers of geometric asymmetry, and unless specifiedotherwise, it is intended that the compounds include both E and Zgeometric isomers. Likewise, all tautomeric forms are also intended tobe included.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. The present disclosure contemplatesvarious stereoisomers and mixtures thereof and includes “enantiomers”,which refers to two stereoisomers whose molecules arenon-superimposeable mirror images of one another.

A “tautomer” refers to a proton shift from one atom of a molecule toanother atom of the same molecule. The present disclosure includestautomers of any said compounds.

An “isotopically enriched derivative” refers to a compound wherein oneor more atoms are replaced by atoms having the same atomic number but anatomic mass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes suitable for inclusion inthe compounds of the disclosure comprises isotopes of hydrogen, such as²H and ³H, carbon, such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁸Cl,fluorine, such as ¹⁸F, iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as¹³N and ¹⁵N, oxygen, such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³¹P,³²P and ³³P, and sulphur, such as ³⁵S. Substitution with heavierisotopes such as deuterium, i.e. ²H, may afford certain therapeuticadvantages resulting from greater metabolic stability, for example,increased in vivo half-life or reduced dosage requirements and hence maybe preferred in some circumstances. Isotopically-enriched compounds ofthe disclosure can generally be prepared by conventional techniquesknown to those skilled in the art or by processes analogous to thosedescribed in the accompanying Examples and Preparations Sections usingan appropriate isotopically-enriched reagent in place of thenon-enriched reagent previously employed.

Where a bond is shown as a dashed line ( - - - ), it is understood thatthe location allows for the possibility of a double bond. For example,the structure of the linker W is shown as:

in which each dash bond may, but not necessarily, indicate the presenceof a double bond. For instance, when A is —NH═, A is connected to thetwo adjacent carbon atoms by a single bond and a double bond,respectively. On the other hand, if A is defined as —O—, A is connectedto the two adjacent carbon atoms by single bonds, respectively. Thelocation and number of the double bonds in a given ring structure of Wshould satisfy the valence requirement, as would be recognized by askilled person in the art.

The chemical naming protocol and structure diagrams used herein employand rely the chemical naming features as utilized by Chemdraw version12.0.2.1076 (available from Cambridgesoft Corp., Cambridge, Mass.). Forcomplex chemical names employed herein, a substituent group is namedbefore the group to which it attaches. For example, cyclopropylethylcomprises an ethyl backbone with cyclopropyl substituent. In chemicalstructure diagrams, all bonds are identified, except for some carbonatoms which are assumed to be bonded to sufficient hydrogen atoms tocomplete the valency.

For example, a compound of formula (I), as set forth above in theSummary of this disclosure, where W is a divalent oxazolyl moietyconnected to the 2-aminopyridine moiety and the R¹ group at 2 and 5positions:

L is 1H-pyrazol-4-yl, R¹ is 4-chlorophenyl, R² is 1-(piperidin-4-yl),R³, R⁴ and R⁵ are each hydrogen, i.e., a compound of the followingformula:

is named herein as:3-(5-(4-chlorophenyl)oxazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine.

It should be note that there are two possible ways for W to connect withthe 2-aminopyridine moiety and the R¹ group, namely, the oxazolyl may beconnected at its 2 position to the 2-aminopyridine moiety, as shownabove; or the oxazolyl may be connected at its 5 position to the2-aminopyridine moiety. Thus, the following compound is also encompassedby Formula (I), when L is 1H-pyrazol-4-yl, R¹ is 4-chlorophenyl, R² is1-(piperidin-4-yl), and R³, R⁴ and R⁵ are hydrogens:

Similarly, the linker L, which is a divalent radical, may also have twopossible ways to connect the 2-aminopyridine and the R² group. Forinstance, when L is an amido linker, i.e., —CON(R⁶)—, a compound ofFormula (I) may have the carbonyl portion directly connected to the2-aminopyridine moiety. Another compound of Formula (I) may have thecarbonyl portion directly connected to the R² group.

As another example, a compound of formula (I), as set forth above in theSummary of this disclosure, where W is a divalent 1,3,4-oxadiazolylmoiety connected to the 2-aminopyridine moiety and the R¹ group at 2 and5 positions:

L is 1H-pyrazol-4-yl, R¹ is 2,6-dichlorophenyl, R² is1-(piperidin-4-yl), R³ and R⁴ are each hydrogen, i.e., a compound of thefollowing formula:

is named herein as:3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine.

Embodiments

Provided herein are aminopyridine derivatives useful as TAM familykinase inhibitors. One embodiment provides a compound of formula (I):

wherein:

W is

each A, A¹ and A² is the same or different and independently —N═, —CR⁵═,or —O—;

L is a heteroaryl, heterocyclyl, —N(R⁶)—, —O—, —C(O)—, —C(O)O—,—S(O)_(t)— where t is 0, 1, or 2, —CON(R⁶)—, —N(R⁶)CO—, —SO₂N(R⁶)—, or—N(R⁶)CON(R⁶)—; provided that when L is heteroaryl, L is not pyridinyl,pyrazinyl or thienyl;

R¹ is alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R² is hydrogen, heterocyclyl, heterocyclylalkyl, cycloalkyl, alkyl,aralkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, or aryl;

each R³ and R⁴ is the same or different and independently selected fromhydrogen, alkyl, aralkyl, alkenyl, aralkenyl, alkynyl, aralkynyl,cycloalkyl, cycloalkylalkyl, halo, and haloalkyl;

R⁵, at each occurrence, is hydrogen, alkyl, aralkyl, cycloalkyl,cycloalkylalkyl, halo, or haloalkyl;

R⁶ is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, or haloalkyl,

a stereoisomer, enantiomer or tautomer thereof, an isotopically enrichedderivative thereof, a pharmaceutically acceptable salt thereof, apharmaceutical composition thereof or a prodrug thereof.

In a further embodiment, L is heteroaryl.

In yet another embodiment, L is N-heteroaryl.

In yet another embodiment, L is divalent pyrrozolyl moiety. In aspecific embodiment, L is 1H-pyrazol-4-yl, and the compound of Formula(I) is represented by Formula (IA):

wherein,

A, A¹, A², R¹, R³, and R⁴ are as defined above.

Of the compounds of Formula (IA), an embodiment provides compounds ofFormula (IA1):

wherein:

R¹, R², R³, and R⁴ are as defined above.

In more specific embodiments of Formula (IA1), R¹ is aryl, heteroaryl,cycloalkyl or heterocyclyl.

In a more specific embodiment of Formula (IA1), R¹ is aryl. Morespecifically, R¹ is a phenyl or substituted phenyl.

In other embodiments of Formula (IA1), R² is aryl, heteroaryl,cycloalkyl or heterocyclyl.

In a more specific embodiment of Formula (IA1), R² is heterocyclyl.

In more specific embodiments of Formula (IA1), R² is N-heterocyclyl.More specifically, R² is piperidinyl or substituted piperidinyl.

In other more specific embodiments of Formula (IA1), R² istetrahydropyranyl.

In another more specific embodiment of Formula (IA1), R² is cyclohexyl.

In certain specific embodiments of Formula (IA1), each of R³ and R⁴ ishydrogen, R¹ is aryl, R² is heterocyclyl.

In certain specific embodiments of Formula (IA1), each of R³ and R⁴ ishydrogen, R¹ is phenyl or substituted phenyl, R² is heterocyclyl.

In certain specific embodiments of Formula (IA1), each of R³ and R⁴ ishydrogen, R¹ is phenyl or substituted phenyl, R² is piperidinyl orsubstituted piperidinyl.

In certain specific embodiments, each of R³ and R⁴ is hydrogen, R¹ isphenyl (including phenyl substituted with one or more halo), and R² isheterocyclyl. In more specific embodiments, R² is a 1-piperidin-4-yl(including 1-piperidin-4-yl substituted at the 1-position with alkyl oracyl).

In various specific embodiments, the compound of Formula (IA1) is:

-   tert-butyl-4-(4-(6-amino-5-(5-phenyloxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;-   3-(5-phenyloxazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;-   tert-butyl    4-(4-(6-amino-5-(5-(4-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;-   3-(5-(4-chlorophenyl)oxazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;-   1-(4-(4-(6-amino-5-(5-(4-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanone;-   (4-(4-(6-amino-5-(5-(4-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(cyclopropyl)methanone;-   3-(5-(3-chlorophenyl)oxazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;-   1-(4-(4-(6-amino-5-(5-(3-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanone;-   3-(5-(3-chlorophenyl)oxazol-2-yl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;-   (4-(4-(6-amino-5-(5-(3-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(cyclopropyl)methanone;-   (4-(4-(6-amino-5-(5-(3-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(phenyl)methanone;-   1-(4-(4-(6-amino-5-(5-(3-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-phenylethanone;-   (4-(4-(6-amino-5-(5-(4-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(phenyl)methanone;-   1-(4-(4-(6-amino-5-(5-(4-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-phenylethanone;-   3-(5-(4-chlorophenyl)oxazol-2-yl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;-   1-(4-(4-(6-amino-5-(5-(3-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2,2-dimethylpropan-1-one;-   (4-(4-(6-amino-5-(5-(3-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(4-fluorophenyl)methanone;    or-   5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-phenyloxazol-2-yl)pyridin-2-amine.

In other more specific embodiments of Formula (IA1), each of R³ and R⁴is hydrogen, R¹ is phenyl or substituted phenyl, R² istetrahydropyranyl.

In various specific embodiments, the compound of Formula (IA1) is:

-   3-(5-phenyloxazol-2-yl)-5-(1-(tetrahydro-2pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;    or-   3-(5-(4-chlorophenyl)oxazol-2-yl)-5-(1-(tetrahydro-2pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine.

In other more specific embodiments of Formula (IA1), each of R³ and R⁴is hydrogen, R¹ is phenyl or substituted phenyl, R² is cyclohexyl.

In various specific embodiments, the compound of Formula (IA1) is:

-   3-(5-(3-chlorophenyl)oxazol-2-yl)-5-(1-cyclohexyl-1H-pyrazol-4-yl)pyridin-2-amine;-   3-(5-(4-chlorophenyl)oxazol-2-yl)-5-(1-cyclohexyl-1H-pyrazol-4-yl)pyridin-2-amine;    or-   5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(5-phenyloxazol-2-yl)pyridin-2-amine.

In other embodiments, each of R³ and R⁴ is hydrogen, R¹ is heteroaryl(e.g., pyridinyl), and R² is heterocyclyl.

In more specific embodiments, the compound is5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-(pyridin-3-yl)oxazol-2-yl)pyridin-2-amine.

Of the compounds of Formula (IA), another embodiment provides compoundsof Formula (IA2):

wherein, R¹, R², R³, and R⁴ are as defined above.

In more specific embodiments of Formula (IA2), R¹ is aryl, heteroaryl,cycloalkyl or heterocyclyl. More specifically, R¹ is aryl. Morespecifically, R¹ is a phenyl or substituted phenyl.

In other embodiments of Formula (IA2), R² is aryl, heteroaryl,cycloalkyl or heterocyclyl. More specifically, R² is heterocyclyl. Morespecifically, R² is N-heterocyclyl.

In certain specific embodiments of Formula (IA2), each of R³ and R⁴ ishydrogen, R¹ is phenyl or substituted phenyl, R² is piperidinyl orsubstituted piperidinyl, tetrahydropyranyl or cyclohexyl.

In various specific embodiments, the compound of Formula (IA2) is:

-   5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(5-phenylisoxazol-3-yl)pyridin-2-amine;-   3-(5-phenylisoxazol-3-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;-   3-(5-phenylisoxazol-3-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;    or-   5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-phenylisoxazol-3-yl)pyridin-2-amine.

Of the compounds of Formula (IA), another embodiment provides compoundsof Formula (IA3):

wherein, R¹, R², R³, and R⁴ are as defined above.

In more specific embodiments of Formula (IA3), R¹ is aryl, heteroaryl,cycloalkyl or heterocyclyl. More specifically, R¹ is aryl. Morespecifically, R¹ is a phenyl or substituted phenyl.

In other embodiments of Formula (IA3), R² is aryl, heteroaryl,cycloalkyl or heterocyclyl. More specifically, R² is heterocyclyl. Morespecifically, R² is N-heterocyclyl.

In certain specific embodiments of Formula (IA3), each of R³ and R⁴ ishydrogen, R¹ is phenyl or substituted phenyl, R² is piperidinyl orsubstituted piperidinyl, tetrahydropyranyl or cyclohexyl.

In various specific embodiments, the compound of Formula (IA3) is:

-   3-(5-phenylfuran-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;-   5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-phenylfuran-2-yl)pyridin-2-amine;-   5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(5-phenylfuran-2-yl)pyridin-2-amine;    or-   3-(5-phenylfuran-2-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine.

Of the compounds of Formula (IA), another embodiment provides compoundsof Formula (IA4):

wherein, R¹, R², R³, and R⁴ are as defined above.

In more specific embodiments of Formula (IA4), R¹ is aryl, heteroaryl,cycloalkyl, heterocyclyl, aralkyl, or cycloalkylalkyl.

In a more specific embodiment of Formula (IA4), R¹ is aryl. Morespecifically, R¹ is a phenyl or substituted phenyl.

In another more specific embodiment of Formula (IA4), R¹ is heteroaryl.More specifically, R¹ is a pyridinyl, substituted pyridinyl, pyrazinyl,substituted pyrazinyl, thiazolyl, substituted thiazolyl.

In further specific embodiment of Formula (IA4), R¹ is aralkyl. Morespecifically, R¹ is benzyl.

In further specific embodiment of Formula (IA4), R¹ is cycloalkylalkyl.More specifically, R¹ is cycloalkylalkyl.

In any of the above embodiments of Formula (IA4), R² is hydrogen, aryl,heteroaryl, cycloalkyl or heterocyclyl.

In a more specific embodiment of Formula (IA4), R² is heterocyclyl. Morespecifically, R² is N-heterocyclyl.

In more specific embodiments of Formula (IA4), R² is piperidinyl orsubstituted piperidinyl.

In other more specific embodiments of Formula (IA4), R² istetrahydropyranyl.

In other more specific embodiments of Formula (IA4), R² is hydrogen.

In certain specific embodiments of Formula (IA4), each of R³ and R⁴ ishydrogen, R¹ is aryl, R² is heterocyclyl, including N-heterocyclyl.

In certain specific embodiments of Formula (IA4), each of R³ and R⁴ ishydrogen, R¹ is phenyl or phenyl substituted with one or more halo oralkyl, R² is piperidinyl or substituted piperidinyl.

In various specific embodiments, a compound of Formula (IA4) is:

-   tert-butyl    4-(4-(6-amino-5-(5-phenyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;-   3-(5-phenyl-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;-   3-(5-(2,6-dichloro-3-fluorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;-   3-(5-(4-(tert-butyl)phenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;-   tert-butyl    4-(4-(6-amino-5-(5-(4-(tert-butyl)phenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;-   3-(5-(2,5-difluorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;-   3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;-   tert-butyl    4-(4-(6-amino-5-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;-   3-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;-   tert-butyl    4-(4-(6-amino-5-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;-   1-(4-(4-(6-amino-5-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanone;-   3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;-   1-(4-(4-(6-amino-5-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-4-methylpentan-1-one;-   (4-(4-(6-amino-5-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(cyclopropyl)methanone;-   (4-(4-(6-amino-5-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(phenyl)methanone;-   1-(4-(4-(6-amino-5-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-phenylethanone;-   3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;    or-   3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(1-dodecylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine.

In other more specific embodiments of Formula (IA4), each of R³ and R⁴is hydrogen, R¹ is heteroaryl or substituted heteroaryl, R² ispiperidinyl or substituted piperidinyl.

In various specific embodiments, the compound of Formula (IA4) is:

-   tert-butyl    4-(4-(6-amino-5-(5-(pyrazin-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;-   tert-butyl    4-(4-(6-amino-5-(5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;-   5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-(pyrazin-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine;-   5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine;-   tert-butyl    4-(4-(6-amino-5-(5-(thiazol-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;-   5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-(thiazol-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine;-   5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine;-   tert-butyl    4-(4-(6-amino-5-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;-   tert-butyl    4-(4-(6-amino-5-(5-(4-(trifluoromethyl)-thiazol-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;    or-   5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-(4-(trifluoromethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine.

In other more specific embodiments of Formula (IA4), each of R³ and R⁴is hydrogen, R¹ is cycloalkylalkyl or aralkyl, R² is piperidinyl orsubstituted piperidinyl.

In various specific embodiments, the compound of Formula (IA4) is:

-   tert-butyl    4-(4-(6-amino-5-(5-(cyclopropylmethyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;-   3-(5-(cyclopropylmethyl)-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;-   tert-butyl    4-(4-(6-amino-5-(5-benzyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;    or-   3-(5-benzyl-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine.

In other more specific embodiments of Formula (IA4), each of R³ and R⁴is hydrogen, R¹ is aryl or more specifically phenyl or substitutedphenyl, R² is hydrogen.

In various specific embodiments, the compound of Formula (IA4) is:

-   3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine;-   3-(5-phenyl-1,3,4-oxadiazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine;-   3-(5-(4-(tert-butyl)phenyl)-1,3,4-oxadiazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine;-   3-(5-(2,5-difluorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine;    or-   3-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine.

In other more specific embodiments of Formula (IA4), each of R³ and R⁴is hydrogen, R¹ is aryl or more specifically, phenyl or substitutedphenyl, R² is cycloalkyl.

In a specific embodiment, the compound of Formula (IA4) is:

-   5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine;-   5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyridin-2-amine.

In yet other more specific embodiments of Formula (IA4), each of R³ andR⁴ is hydrogen, R¹ is aryl or more specifically, phenyl or substitutedphenyl, R² is tetrahydropyranyl.

In a specific embodiment, the compound of Formula (IA4) is:

-   3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;    or-   3-(5-phenyl-1,3,4-oxadiazol-2-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine.

Of the compounds of Formula (IA), another embodiment provides compoundsof Formula (IA5):

In a more specific embodiment of Formula (IA5), R¹ is aryl. Morespecifically, R¹ is a phenyl or substituted phenyl.

In a more specific embodiment of Formula (IA5), R² is heterocyclyl. Morespecifically, R² is N-heterocyclyl.

In more specific embodiments of Formula (IA5), R² is piperidinyl,substituted piperidinyl, tetrahydropyranyl or cyclohexyl.

In other more specific embodiments of Formula (IA5), R² is hydrogen.

In certain specific embodiments of Formula (IA5), each of R³ and R⁴ ishydrogen, R¹ is aryl, R² is heterocyclyl, including N-heterocyclyl.

In yet other more specific embodiments of Formula (IA5), each of R³ andR⁴ is hydrogen, R¹ is aryl or more specifically, phenyl or substitutedphenyl, R² is hydrogen, piperidinyl, substituted piperidinyl,tetrahydropyranyl or cyclohexyl.

In yet other more specific embodiments of Formula (IA5), each of R³ andR⁴ is hydrogen, R¹ is aryl or more specifically, phenyl or substitutedphenyl, R² is piperidinyl, substituted piperidinyl.

In a specific embodiment, the compound of Formula (IA5) is:

-   3-(3-phenyl-1,2,4-oxadiazol-5-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;-   1-(4-(4-(6-amino-5-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanone;-   (4-(4-(6-amino-5-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(cyclopropyl)methanone;-   5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin-2-amine;-   (4-(4-(6-amino-5-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(phenyl)methanone;-   1-(4-(4-(6-amino-5-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-phenylethanone;-   3-(3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;-   3-(3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;-   3-(3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl)-5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;-   5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin-2-amine;    or-   3-(3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl)-5-(1-(1-dodecylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine.

In yet other more specific embodiments of Formula (IA5), each of R³ andR⁴ is hydrogen, R¹ is aryl or more specifically, phenyl or substitutedphenyl, R² is hydrogen, tetrahydropyranyl or cyclohexyl.

In a specific embodiment, the compound of Formula (IA5) is:

-   5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin-2-amine;-   5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl)pyridin-2-amine;-   3-(3-phenyl-1,2,4-oxadiazol-5-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;-   3-(3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;    or-   3-(3-phenyl-1,2,4-oxadiazol-5-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine.

Of the compounds of Formula (IA), another embodiment provides compoundsof Formula (IA6):

wherein, R¹, R², R³, and R⁴ are as defined above.

In a more specific embodiment of Formula (IA6), R¹ is aryl. Morespecifically, R¹ is a phenyl or substituted phenyl.

In a more specific embodiment of Formula (IA6), R² is heterocyclyl. Morespecifically, R² is N-heterocyclyl.

In more specific embodiments of Formula (IA6), R² is piperidinyl orsubstituted piperidinyl, tetrahydropyranyl or cyclohexyl.

In other more specific embodiments of Formula (IA6), R² is hydrogen.

In certain specific embodiments of Formula (IA6), each of R³ and R⁴ ishydrogen, R¹ is aryl, R² is heterocyclyl, including N-heterocyclyl.

In yet other more specific embodiments of Formula (IA6), each of R³ andR⁴ is hydrogen, R¹ is aryl or more specifically, phenyl or substitutedphenyl, R² is hydrogen, piperidinyl, substituted piperidinyl,tetrahydropyranyl or cyclohexyl.

In a specific embodiment, the compound of Formula (IA6) is:

-   5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(5-phenyl-1,2,4-oxadiazol-3-yl)pyridin-2-amine;-   3-(5-phenyl-1,2,4-oxadiazol-3-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;-   3-(5-phenyl-1,2,4-oxadiazol-3-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;-   5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-phenyl-1,2,4-oxadiazol-3-yl)pyridin-2-amine;-   3-(5-(2,5-dichlorophenyl)-1,2,4-oxadiazol-3-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;-   3-(5-phenyl-1,2,4-oxadiazol-3-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine.

Of the compounds of Formula (IA), another embodiment provides compoundsof Formula (IA7):

wherein, R¹, R², R³, and R⁴ are as defined above. In a more specificembodiment of Formula (IA7), R¹ is aryl. More specifically, R¹ is aphenyl or substituted phenyl.

In a more specific embodiment of Formula (IA7), R² is heterocyclyl. Morespecifically, R² is piperidinyl or substituted piperidinyl.

In a specific embodiment, the compound of Formula (IA7) is:

-   3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrrol-3-yl)pyridin-2-amine.

Of the compounds of Formula (I), an embodiment provides compound ofFormula (IB):

wherein,

A, A¹, A², R¹, R³, R⁴, and R⁵ are as defined above,

L is heteroaryl or heterocycle;

R⁷ is hydrogen, alkyl, alkoxy, or halo;

X is —O—, —NR⁸—, or —C(R⁹)₂—;

R⁸ is hydrogen, alkyl, or —C(O)R¹⁰—;

each R⁹ is independently hydrogen, alkyl, alkoxy, or halo; and

R¹⁰ is alkyl, cycloalkyl, aryl, alkoxy, or aralkyl.

Of the compounds of Formula (IB), an embodiment provides compound ofFormula (IB1):

wherein,

each A, A¹ and A² is the same or different and independently —N═, —CR⁵═,or —O—;

R¹ is aryl, heteroaryl, cycloalkyl, heterocyclyl, aralkyl, orcycloalkylalkyl;

each of R³, R⁴ and R⁷ is hydrogen,

R⁸ is hydrogen, alkyl, or —C(O)R¹⁰—; and

R¹⁰ is alkyl, cycloalkyl, aryl, alkoxy, or aralkyl.

In a more specific embodiment of Formula (IB1), R¹ is aryl. Morespecifically, R¹ is a phenyl or substituted phenyl.

In another more specific embodiment of Formula (IB1), R¹ is heteroaryl.More specifically, R¹ is a pyridinyl, substituted pyridinyl, pyrazinyl,substituted pyrazinyl, thiazolyl, substituted thiazolyl.

In further specific embodiment of Formula (IB1), R¹ is aralkyl. Morespecifically, R¹ is benzyl.

In further specific embodiment of Formula (IB1), R¹ is cycloalkylalkyl.More specifically, R¹ is cyclopropylalkyl.

Of the compounds of Formula (IB), an embodiment provides compound ofFormula (IB2):

wherein,

each A, A¹ and A² is the same or different and independently —N═, —CR⁵═,or —O—;

R¹ is aryl, heteroaryl, cycloalkyl, or heterocyclyl; and

each of R³, R⁴ and R⁷ is hydrogen.

In a more specific embodiment of Formula (IB2), R¹ is aryl. Morespecifically, R¹ is a phenyl or substituted phenyl.

Of the compounds of Formula (IB), an embodiment provides compound ofFormula (IB3):

wherein,

each A, A¹ and A² is the same or different and independently —N═, —CR⁵═,or —O—;

R¹ is aryl, heteroaryl, cycloalkyl, or heterocyclyl; and

each of R³, R⁴, R⁷ and R⁹ is hydrogen;

In a more specific embodiment of Formula (IB3), R¹ is aryl. Morespecifically, R¹ is a phenyl or substituted phenyl.

Utility and Testing of the Compounds of the Disclosure

The present disclosure relates to compounds, pharmaceutical compositionsand methods of using the compounds and pharmaceutical compositions forthe treatment and/or prevention of diseases and conditions mediated bythe kinase activity of Tyro3, Axl or Mer individually or by anycombination of them, preferably diseases and conditions related tocharacterized by angiogenesis and/or cell proliferation and migration,and especially a disease and condition related to cancer, inflammatorydiseases, autoimmune diseases, neurodisorders, and the like, byadministering an effective amount of a compound of the disclosure.

The compounds of the disclosure modulate, preferably inhibit, theactivity of human Tyro3, Axl or Mer individually or by any combinationof them.

The general value of the compounds of the disclosure in modulating,especially inhibiting, the activity of Tyro3, Axl or Mer individually orby any combination of them can be determined using the assay describedbelow in Example 21.

The compounds of the instant disclosure are inhibitors of Tyro3, Axl orMer individually or inhibitors of any combination of them and are usefulfor treating diseases and disorders in humans and other organisms,including all those human diseases and disorders which are the result ofabnormal kinase activity of Tyro3, Axl or Mer individually or anycombination of them or which may be ameliorated by modulation of thekinase activity of Tyro3, Axl or Mer individually or any combination ofthem.

As defined herein, a disease or condition mediated by the abnormalkinase activity of Tyro3, Axl or Mer individually or any combination ofthem is defined as any disease or condition in which the activity ofTyro3, Axl or Mer individually or any combination of them is elevatedand/or where inhibition of the activity of Tyro3, Axl or Merindividually or any combination of them can be demonstrated to bringabout symptomatic improvements for the individual so treated. As definedherein, a disease or condition mediated by the abnormal activity ofTyro3, Axl or Mer individually or any combination of them includes, butis not limited to, a disease or condition which is, or is related tocancer, inflammatory diseases, autoimmune diseases, and neurodisorders.For purposes of this disclosure, Diseases and conditions which arealleviated by the modulation of the activity of Tyro3, Axl or Merindividually or any combination of them include, but are not limited to,solid tumors, including, but not limited to, breast, renal, endometrial,ovarian, thyroid, and non-small cell lung carcinoma, melanoma, prostatecarcinoma, sarcoma, gastric cancer and uveal melanoma; liquid tumors,including but not limited to, leukemias particularly myeloid leukemiasand lymphomas; endometriosis, vascular disease/injury including, but notlimited to, restenosis, atherosclerosis and thrombosis, psoriasis;visual impairment due to macular degeneration; diabetic retinopathy andretinopathy of prematurity; kidney disease including, but not limitedto, glomerulonephritis, diabetic nephropathy and renal transplantrejection, rheumatoid arthritis; osteoarthritis, osteoporosis andcataracts.

In addition to the foregoing, the compounds of the disclosure are usefulin treating diseases and conditions which are affected by the followingbiological processes: Invasion, migration, metastasis, or drugresistance as manifested in cancer; stem cell biology as manifested incancer; invasion, migration, adhesion, or angiogenesis as manifested inendometriosis; vascular remodeling as manifested in cardiovasculardisease, hypertension or vascular injury; bone homeostatasis asmanifested in osteoporosis or osteoarthritis; viral infection asmanifested, for example, in ebola virus infection; or differentiation asmanifested in obesity. The compounds of the disclosure may also be usedto modulate inflammatory processes by treating sepsis, acting as vaccineadjuvants, and/or potentiating the immune response in immuno-compromisedpatients.

The following animal models provide guidance to one of ordinary skill inthe art in testing the compounds of the disclosure for their use intreating the disease or condition indicated.

The compounds of the disclosure may be used or tested for their use intreating leukemias and lymphomas by, respectively, administering apharmaceutically effective amount or testing the compounds in thexenograft in SCID mouse model using human cancer cell lines whichexpress Tyro3 or Axl or Mer or co-expressing any combination of thesethree kinases including, but not limited to, A549, K562, HeLa,MDA-MB-231, SK-OV-3, OVCAR-8, DU145, H1299, ACHN, A498 and Caki-1.

The compounds of the disclosure may be tested for their use in treatingleukemias in the xenograft in SCID or nu/nu mouse model using human AMLand CML leukemia cell lines.

The compounds of the disclosure may be used or tested for their use intreating endometriosis by, respectively, administering apharmaceutically effective amount to a subject in need thereof or usingthe syngenic mouse model of endometriosis (see Somigliana, E. et al.,“Endometrial ability to implant in ectopic sites can be prevented byinterleukin-12 in a murine model of endometriosis”, Hum. Reprod. 1999,14(12), 2944-2950). The compounds may also be tested for their use intreating endometriosis by using the rat model of endometriosis (seeLebovic, D. I. et al., “Peroxisome proliferator-activated receptor-gammainduces regression of endometrial explants in a rat model ofendometriosis”, Feral. Steril., 2004, 82 Suppl 3, 1008-1013).

The compounds of the disclosure may be used or tested for their use intreating restenosis by, respectively, by administering apharmaceutically effective amount to a subject in need thereof or usingthe balloon-injured rate carotid artery model (see Kim, D. W. et al.,“Novel oral formulation of paclitaxel inhibits neointimal hyperplasia ina rat carotid artery injury model”, Circulation, 2004, 109(12),1558-1563). The compounds of the disclosure may also be tested for theiruse in treating restenosis by using the percutaneous transluminalcoronary angioplasty in apoE deficient mouse model (see von der Thusen,J. H. et al., “Adenoviral transfer of endothelial nitric oxide synthaseattenuates lesion formation in a novel murine model of postangioplastyrestenosis”, Arterioscler. Thromb. Vase. Biol., 2004, 24(2), 357-362).

The compounds of the disclosure may be used or tested for their use intreating atherosclerosis/thrombosis, respectively, by administering apharmaceutically effective amount to a subject in need thereof or in theApoE deficient mouse model (see Nakashima, Y. et al., “ApoE-deficientmice develop lesions of all phases of atherosclerosis throughout thearterial tree”, Arterioscler. Thromb., 1994, 14(1), 133-140).

The compounds of the disclosure may also be used or tested for their usein treating thrombosis, respectively, by administering apharmaceutically effective amount to a subject in need thereof or usingthe collagen-epinephrine-induced pulmonary thromboembolism model and thestasis induced venous thrombosis model (see Angelillo-Scherrer A. etal., “Role of Gas6 receptors in platelet signaling during thrombusstabilization and implications for antithrombotic therapy”, J. Clin.Invest., 2005,115, 237-246).

The compounds of the disclosure may be used or tested for their use intreating psoriasis by, respectively, by administering a pharmaceuticallyeffective amount to a subject in need thereof or using the SCID mousemodel or the human skin model of psoriasis (see Nickoloff, B. J. et al.,“Severe combined immunodeficiency mouse and human psoriatic skinchimeras. Validation of a new animal model”, Am. J. Pathol., 1995,146(3), 580-588).

The compounds of the disclosure may be used or tested for their use intreating age-related macular degeneration or diabetic retinopathy by,respectively, administering a pharmaceutically effective amount to asubject in need thereof or using the rat corneal angiogenesis model (seeSarayba M A, Li L, Tungsiripat T, Liu N H, Sweet P M, Patel A J, Osann KE, Chittiboyina A, Benson S C, Pershadsingh H A, Chuck R S. Inhibitionof corneal neovascularization by a peroxisome proliferator-activatedreceptor-gamma ligand. Exp. Eye. Res., 2005, 80(3), 435-442) or thelaser-induced mouse choroidal neovasculation model (see Bora, P. S., etal., “Immunotherapy for choroidal neovascularization in a laser-inducedmouse model simulating exudative (wet) macular degeneration”, Proc.Natl. Acad. Sci. U.S.A., 2003, 100(5), 2679-2684).

The compounds of the disclosure may be used or tested for their use intreating retinopathy of prematurity, respectively, by administering apharmaceutically effective amount to a subject in need thereof or in themouse retinopathy of prematurity model (see Smith, L. E. et al.,“Oxygen-induced retinopathy in the mouse”, Invest. Ophthalmol. Vis.Sci., 1994, 35(1), 101-111). The compounds of the disclosure may betested for their use in treating glomerulonephritis or diabeticnephropathy in the rat anti-Thyl.1-induced experimental mesengialproliferative glomerulonephritis model (see Smith, L. E. et al. citedabove).

The compounds of the disclosure may be used or tested for their use intreating renal transplant rejection, respectively, by administering apharmaceutically effective amount to a subject in need thereof or byusing a rat model of chronic renal transplant rejection (see Yin, J. L.et al., “Expression of growth arrest-specific gene 6 and its receptorsin a rat model of chronic renal transplant rejection”, Transplantation,2002, 73(4), 657-660).

The compounds of the disclosure may be used or tested for their use intreating rheumatoid arthritis by, respectively, administering apharmaceutically effective amount to a subject in need thereof or usingthe CAIA mouse model (see Phadke, K. et al., “Evaluation of the effectsof various anti-arthritic drugs on type Il collagen-induced mousearthritis model”, Immunopharmacology, 1985, 10(1), 51-60).

The compounds of the disclosure may be used or tested for their use intreating osteoarthritis by, respectively, administering apharmaceutically effective amount to a subject in need thereof or usingthe STR/ORT mouse model (see Brewster, M. et al., “Ro 32-3555, an orallyactive collagenase selective inhibitor, prevents structural damage inthe STR/ORT mouse model of osteoarthritis”, Arthritis. Rheum., 1998,41(9), 1639-1644).

The compounds of the disclosure may be used or tested for their use intreating osteoporosis by, respectively, administering a pharmaceuticallyeffective amount to a subject in need thereof or using theovariectomized rat model (see Wronski, T J. et al., “Endocrine andpharmacological suppressors of bone turnover protect against osteopeniain ovariectomized rats”, Endocrinology, 1989, 125(2), 810-816) or theovariectomized mouse model (see Alexander, J. M. et al., “Humanparathyroid hormone 1-34 reverses bone loss in ovariectomized mice”, JBone Miner Res., 2001, 16(9), 1665-1673; Fujioka, M. et al., “Equol, ametabolite of daidzein, inhibits bone loss in ovariectomized mice”, J.Nut., 2004, 134(10), 2623-2627).

The compounds of the disclosure may be used or tested for their use intreating cataracts by, respectively, administering a pharmaceuticallyeffective amount to a subject in need thereof or using the H₂O₂-inducedmodel (see Kadoya, K. et al., “Role of calpain in hydrogen peroxideinduced cataract”, Curr. Eye Res., 1993, 12(4), 341-346) or the Emorymouse model (see Sheets, N. L. et al., “Cataract- and lens-specificup-regulation of ARK receptor tyrosine kinase in Emory mouse cataract”,Invest. Ophthalmol. Vis. Sci., 2002, 43(6), 1870-1875).

Typically, a successful inhibitory therapeutic agent of the activity ofTyro3, Axl or Mer individually or any combination of them will meet someor all of the following criteria. Oral availability should be at orabove 20% Animal model efficacy is less than about 20 mg/Kg, 2 mg/Kg, 1mg/Kg, or 0.5 mg/Kg and the target human dose is between 10 and 250mg/70 Kg, although doses outside of this range may be acceptable.(“mg/Kg” means milligrams of compound per kilogram of body mass of thesubject to whom it is being administered). The required dosage shouldpreferably be no more than about once or twice a day or at meal times.The therapeutic index (or ratio of toxic dose to therapeutic dose)should be greater than 10. The IC₅₀ (“Inhibitory Concentration—50%”) isa measure of the amount of compound required to achieve 50% inhibitionof the kinase activity, over a specific time period, in a kinaseactivity assay. Any process for measuring the kinase activity of Tyro3,Axl or Mer, preferably human Tyro3, Axl or Mer, may be utilized to assaythe activity of the compounds useful in the methods of the disclosure ininhibiting said Tyro3, Axl or Mer activity. Compounds of the disclosuredemonstrate an IC₅₀ in a 15 to 60 minute recombinant human kinase assayof preferably less than 10 mM, less than 5 μM, less than 2.5 μM, lessthan 1 μM. less than 750 nM, less than 500 nM, less than 250 nM, lessthan 100 nM, less than 50 nM, and most preferably less than 20 nM.Compounds of the disclosure may show reversible inhibition (i.e.competitive inhibition) or irreversible inhibition and preferably do notinhibit other protein kinases.

The identification of compounds of the disclosure as Tyro3, Axl or Merinhibitors was readily accomplished using the recombinant human Tyro3,Axl and Mer proteins and employing the ³³P-radiolabeled phosphatetransfer assay for which the procedure is known to someone skilled inthe art or as described in Example 18. When tested in this assay,compounds of the disclosure had greater than 50% inhibitory activity at10 μM concentration of the test compound, preferably greater than 60%inhibitory activity at 10 μM concentration of the test compound, morepreferably greater than 70% inhibitory activity at 10 μM concentrationof the test compound, and even more preferably greater than 80%inhibitory activity at 10 μM concentration of the test compound, and themost preferably greater than 90% inhibitory activity at 10 μMconcentration of the test compound, thereby demonstrating that thecompounds of the disclosure are potent inhibitors of the kinase activityof Tyro3, Axl and Mer.

These results provide the basis for analysis of the structure-activityrelationship (SAR) between test compounds and the kinase activity ofTyro3, Axl and Mer. Certain-groups tend to provide more potentinhibitory compounds. SAR analysis is one of the tools those skilled inthe art may employ to identify preferred embodiments of the compounds ofthe disclosure for use as therapeutic agents. Other methods of testingthe compounds disclosed herein are also readily available to thoseskilled in the art. Thus, in addition, the determination of the abilityof a compound to inhibit Tyro3, Axl and Mer activity may be accomplishedin vivo. In one such embodiment this is accomplished by administeringsaid chemical agent to an animal afflicted with a certain tumor graftmodel and subsequently detecting a change in tumor growth rate in saidanimal thereby identifying a therapeutic agent useful in treating thesaid tumors. In such embodiment, the animal may be a human, such as ahuman patient afflicted with such a disorder and in need of treatment ofsaid disorder.

In specific embodiments of such in vivo processes, said change in Tyro3,Axl or Mer activity in said animal is a decrease in activity, preferablywherein said Tyro3, Axl or Mer inhibiting agent does not substantiallyinhibit the biological activity of other kinases.

The compounds of the disclosure can be used in combination with othertherapeutic agents. Examples of alkylating agents that can be carriedout in combination with include, but not limited to, fluorouracil (5-FU)alone or in further combination with leukovorin; other pyrimidineanalogs such as UFT, capecitabine, gemcitabine and cytarabine, the alkylsulfonates, e.g., busulfan (used in the treatment of chronicgranulocytic leukemia), improsulfan and piposulfan; aziridines, e.g.,benzodepa, carboquone, meturedepa and uredepa; ethyleneimines andmethylmelamines, e.g., altretamine, triethylenemelamine,triethylenephosphoramide, triethylenethiophosphoramide andtrimethylolmelamine; and the nitrogen mustards, e.g., chlorambucil (usedin the treatment of chronic lymphocytic leukemia, primarymacroglobulinemia and non-Hodgkin's lymphoma), cyclophosphamide (used inthe treatment of Hodgkin's disease, multiple myeloma, neuroblastoma,breast cancer, ovarian cancer, lung cancer, Wilm's tumor andrhabdomyosarcoma), estramustine, ifosfamide, novembrichin, prednimustineand uracil mustard (used in the treatment of primary thrombocytosis,non-Hodgkin's lymphoma, Hodgkin's disease and ovarian cancer); andtriazines, e.g., dacarbazine (used in the treatment of soft tissuesarcoma).

Examples of antimetabolite chemotherapeutic agents that can be carriedout in combination with include, but not limited to, folic acid analogs,e.g., methotrexate (used in the treatment of acute lymphocytic leukemia,choriocarcinoma, mycosis fungiodes, breast cancer, head and neck cancerand osteogenic sarcoma) and pteropterin; and the purine analogs such asmercaptopurine and thioguanine which find use in the treatment of acutegranulocytic, acute lymphocytic and chronic granulocytic leukemias.Examples of natural product-based chemotherapeutic agents that can becarried out in combination with include, but not limited to, the vincaalkaloids, e.g., vinblastine (used in the treatment of breast andtesticular cancer), vincristine and vindesine; the epipodophyllotoxins,e.g., etoposide and teniposide, both of which are useful in thetreatment of testicular cancer and Kaposi's sarcoma; the antibioticchemotherapeutic agents, e.g., daunorubicin, doxorubicin, epirubicin,mitomycin (used to treat stomach, cervix, colon, breast, bladder andpancreatic cancer), dactinomycin, temozolomide, plicamycin, bleomycin(used in the treatment of skin, esophagus and genitourinary tractcancer); and the enzymatic chemotherapeutic agents such asL-asparaginase.

Examples of other signal transduction inhibiting agents that can becarried out in combination with include, but not limited to, gefltinib,erlotinib, sorafenib, herceptin, imatinib, dasatinib, sunitinib,nilotinib, lapatinib, pazopanib, vandetanib, vemurafenib, crizotinib,ruxolitinib, axitinib, bosutinib, regorafenib, tofacitinib,cabozantinib, ponatinib, dabrafenib, trametinib, and afatinib.

Other agents can be used in combination with the compound of thedisclosure include, but not limited to, COX-II inhibitors, such as, butnot limited to, Vioxx, Celebrex (celecoxib), valdecoxib, paracoxib,rofecoxib; matrix metalloproteinase inhibitors, such as, but not limitedto, AG-3340, RO 32-3555, and RS 13-0830.

Pharmaceutical Compositions of the Disclosure and Administration

The present disclosure also relates to pharmaceutical compositioncontaining the compounds of Formula (I), (IA), (IB) or substructuresthereof disclosed herein. In one embodiment, the present disclosurerelates to a composition comprising compounds of Formula (I), (IA), (IB)or substructures thereof in a pharmaceutically acceptable carrier and inan amount effective to modulate the activity of Tyro3, Axl and Merindividually or in any combination of them or to treat diseases relatedto angiogenesis and/or cell proliferation and migration, and especiallycancer, inflammatory diseases, autoimmune diseases, neurodisorders andthe like when administered to an animal, preferably a mammal, mostpreferably a human patient. In an embodiment of such composition, thepatient has hyperproliferative disease, and especially cancer,inflammatory diseases, autoimmune diseases, neurodisorders and the like,before administration of said compound of the disclosure and thecompound of the disclosure is present in an amount effective to reducesaid lipid level.

The pharmaceutical compositions useful herein also contain apharmaceutically acceptable carrier, including any suitable diluent orexcipient, which includes any pharmaceutical agent that does not itselfinduce the production of antibodies harmful to the individual receivingthe composition, and which may be administered without undue toxicity.Pharmaceutically acceptable carriers include, but are not limited to,liquids, such as water, saline, glycerol and ethanol, and the like. Athorough discussion of pharmaceutically acceptable carriers, diluents,and other excipients is presented in REMINGTON'S PHARMACEUTICAL SCIENCES(Mack Pub. Co., N.J. current edition).

Those skilled in the art are also familiar with determiningadministration methods (oral, intravenous, inhalation, sub-cutaneous,etc.), dosage forms, suitable pharmaceutical excipients and othermatters relevant to the delivery of the compounds to a subject in needthereof.

In an alternative use of the disclosure, the compounds of the disclosurecan be used in in vitro or in vivo studies as exemplary agents forcomparative purposes to find other compounds also useful in treatmentof, or protection from, the various diseases disclosed herein.

Administration of the compounds of the disclosure, or theirpharmaceutically acceptable salts, in pure form or in an appropriatepharmaceutical composition, can be carried out via any of the acceptedmodes of administration of agents for serving similar utilities. Thepharmaceutical compositions of the disclosure can be prepared bycombining a compound of the disclosure with an appropriatepharmaceutically acceptable carrier, diluent or excipient, and may beformulated into preparations in solid, semi-solid, liquid or gaseousforms, such as tablets, capsules, powders, granules, ointments,solutions, suppositories, injections, inhalants, gels, microspheres, andaerosols. Typical routes of administering such pharmaceuticalcompositions include, without limitation, oral, topical, transdermal,inhalation, parenteral, sublingual, buccal, rectal, vaginal, andintranasal. The term parenteral as used herein includes subcutaneousinjections, intravenous, intramuscular, intrasternal injection orinfusion techniques. Pharmaceutical compositions of the disclosure areformulated so as to allow the active ingredients contained therein to bebioavailable upon administration of the composition to a patient.Compositions that will be administered to a subject or patient take theform of one or more dosage units, where for example, a tablet may be asingle dosage unit, and a container of a compound of the disclosure inaerosol form may hold a plurality of dosage units. Actual methods ofpreparing such dosage forms are known, or will be apparent, to thoseskilled in this art; for example, see Remington: The Science andPractice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy andScience, 2000). The composition to be administered will, in any event,contain a therapeutically effective amount of a compound of thedisclosure, or a pharmaceutically acceptable salt thereof, for treatmentof a disease or condition of interest in accordance with the teachingsof this disclosure.

A pharmaceutical composition of the disclosure may be in the form of asolid or liquid. In one aspect, the carrier(s) are particulate, so thatthe compositions are, for example, in tablet or powder form. Thecarrier(s) may be liquid, with the compositions being, for example, anoral oil, injectable liquid or an aerosol, which is useful in, forexample, inhalatory administration.

When intended for oral administration, the pharmaceutical composition ispreferably in either solid or liquid form, where semi-solid,semi-liquid, suspension and gel forms are included within the formsconsidered herein as either solid or liquid.

As a solid composition for oral administration, the pharmaceuticalcomposition may be formulated into a powder, granule, compressed tablet,pill, capsule, chewing gum, wafer or the like form. Such a solidcomposition will typically contain one or more inert diluents or ediblecarriers. In addition, one or more of the following may be present:binders such as carboxymethylcellulose, ethyl cellulose,microcrystalline cellulose, gum tragacanth or gelatin; excipients suchas starch, lactose or dextrins, disintegrating agents such as alginicacid, sodium alginate, Primogel, corn starch and the like; lubricantssuch as magnesium stearate or Sterotex; glidants such as colloidalsilicon dioxide; sweetening agents such as sucrose or saccharin; aflavoring agent such as peppermint, methyl salicylate or orangeflavoring; and a coloring agent.

When the pharmaceutical composition is in the form of a capsule, forexample, a gelatin capsule, it may contain, in addition to materials ofthe above type, a liquid carrier such as polyethylene glycol or oil.

The pharmaceutical composition may be in the form of a liquid, forexample, an elixir, syrup, solution, emulsion or suspension. The liquidmay be for oral administration or for delivery by injection, as twoexamples. When intended for oral administration, preferred compositioncontain, in addition to the present compounds, one or more of asweetening agent, preservatives, dye/colorant and flavor enhancer. In acomposition intended to be administered by injection, one or more of asurfactant, preservative, wetting agent, dispersing agent, suspendingagent, buffer, stabilizer and isotonic agent may be included.

The liquid pharmaceutical compositions of the disclosure, whether theybe solutions, suspensions or other like form, may include one or more ofthe following adjuvants: sterile diluents such as water for injection,saline solution, preferably physiological saline, Ringer's solution,isotonic sodium chloride, fixed oils such as synthetic mono ordiglycerides which may serve as the solvent or suspending medium,polyethylene glycols, glycerin, propylene glycol or other solvents;antibacterial agents such as benzyl alcohol or methyl paraben;antioxidants such as ascorbic acid or sodium bisulfite; chelating agentssuch as ethylenediaminetetraacetic acid; buffers such as acetates,citrates or phosphates and agents for the adjustment of tonicity such assodium chloride or dextrose. The parenteral preparation can be enclosedin ampoules, disposable syringes or multiple dose vials made of glass orplastic. Physiological saline is a preferred adjuvant. An injectablepharmaceutical composition is preferably sterile. A liquidpharmaceutical composition of the disclosure intended for eitherparenteral or oral administration should contain an amount of a compoundof the disclosure such that a suitable dosage will be obtained.Typically, this amount is at least 0.01% of a compound of the disclosurein the composition. When intended for oral administration, this amountmay be varied to be between 0.1 and about 70% of the weight of thecomposition. Preferred oral pharmaceutical compositions contain betweenabout 4% and about 75% of the compound of the disclosure. Preferredpharmaceutical compositions and preparations according to the presentdisclosure are prepared so that a parenteral dosage unit containsbetween 0.01 to 10% by weight of the compound prior to dilution of thedisclosure.

The pharmaceutical composition of the disclosure may be intended fortopical administration, in which case the carrier may suitably comprisea solution, emulsion, ointment or gel base. The base, for example, maycomprise one or more of the following: petrolatum, lanolin, polyethyleneglycols, bee wax, mineral oil, diluents such as water and alcohol, andemulsifiers and stabilizers. Thickening agents may be present in apharmaceutical composition for topical administration. If intended fortransdermal administration, the composition may include a transdermalpatch or iontophoresis device. Topical formulations may contain aconcentration of the compound of the disclosure from about 0.1 to about10% w/v (weight per unit volume). The pharmaceutical composition of thedisclosure may be intended for rectal administration, in the form, forexample, of a suppository, which will melt in the rectum and release thedrug. The composition for rectal administration may contain anoleaginous base as a suitable nonirritating excipient. Such basesinclude, without limitation, lanolin, cocoa butter and polyethyleneglycol. The pharmaceutical composition of the disclosure may includevarious materials, which modify the physical form of a solid or liquiddosage unit. For example, the composition may include materials thatform a coating shell around the active ingredients. The materials thatform the coating shell are typically inert, and may be selected from,for example, sugar, shellac, and other enteric coating agents.Alternatively, the active ingredients may be encased in a gelatincapsule.

The pharmaceutical composition of the disclosure in solid or liquid formmay include an agent that binds to the compound of the disclosure andthereby assists in the delivery of the compound. Suitable agents thatmay act in this capacity include a monoclonal or polyclonal antibody, aprotein or a liposome. The pharmaceutical composition of the disclosuremay consist of dosage units that can be administered as an aerosol. Theterm aerosol is used to denote a variety of systems ranging from thoseof colloidal nature to systems consisting of pressurized packages.Delivery may be by a liquefied or compressed gas or by a suitable pumpsystem that dispenses the active ingredients. Aerosols of compounds ofthe disclosure may be delivered in single phase, bi-phasic, ortri-phasic systems in order to deliver the active ingredient(s).Delivery of the aerosol includes the necessary container, activators,valves, subcontainers, and the like, which together may form a kit. Oneof ordinary skill in the art, without undue experimentation maydetermine preferred aerosols. The pharmaceutical compositions of thedisclosure may be prepared by methodology well known in thepharmaceutical art. For example, a pharmaceutical composition intendedto be administered by injection can be prepared by combining a compoundof the disclosure with sterile, distilled water so as to form asolution. A surfactant may be added to facilitate the formation of ahomogeneous solution or suspension. Surfactants are compounds thatnon-covalently interact with the compound of the disclosure so as tofacilitate dissolution or homogeneous suspension of the compound in theaqueous delivery system.

The compounds of the disclosure, or their pharmaceutically acceptablesalts, are administered in a therapeutically effective amount, whichwill vary depending upon a variety of factors including the activity ofthe specific compound employed; the metabolic stability and length ofaction of the compound; the age, body weight, general health, sex, anddiet of the patient; the mode and time of administration; the rate ofexcretion; the drug combination; the severity of the particular disorderor condition; and the subject undergoing therapy. Generally, atherapeutically effective daily dose is (for a 70 kg mammal) from about0.001 mg/kg (i.e., 0.7 mg) to about 100 mg/kg (i.e., 7.0 gm); preferablya therapeutically effective dose is (for a 70 kg mammal) from about 0.01mg/kg (i.e., 7 mg) to about 50 mg/kg (i.e., 3.5 g); more preferably atherapeutically effective dose is (for a 70 kg mammal) from about 1mg/kg (i.e., 70 mg) to about 25 mg/kg (i.e., 1.75 g).

Compounds of Formula (I), (IA), (IB) or substructures thereof, orpharmaceutically acceptable derivatives thereof, may also beadministered simultaneously with, prior to, or after administration ofone or more other therapeutic agents. Such combination therapy includesadministration of a single pharmaceutical dosage formulation whichcontains a compound of the disclosure and one or more additional activeagents, as well as administration of the compound of the disclosure andeach active agent in its own separate pharmaceutical dosage formulation.For example, a compound of the disclosure and the other active agent canbe administered to the patient together in a single oral dosagecomposition such as a tablet or capsule, or each agent administered inseparate oral dosage formulations. Where separate dosage formulationsare used, the compounds of the disclosure and one or more additionalactive agents can be administered at essentially the same time, i.e.,concurrently, or at separately staggered times, i.e., sequentially;combination therapy is understood to include all these regimens.

Isotopic Enrichment of Compounds Isotopic enrichment is a process bywhich the relative abundance of the isotopes of a given element arealtered, thus producing a form of the element that has been enriched inone particular isotope and depleted in its other isotopic forms.Isotopic enrichment of a drug are used for the following applications:reducing or eliminating unwanted metabolites; increasing the half-lifeof the parent drug; decreasing the number of doses needed to achieve adesired effect; decreasing the amount of a dose necessary to achieve adesired effect; increasing the formation of active metabolites, if anyare formed; and/or decreasing the production of deleterious metabolitesin specific tissues and/or create a more effective drug and/or a saferdrug for combination therapy, whether the combination therapy isintentional or not.

Replacement of an atom for one of its isotopes often will result in achange in the reaction rate of a chemical reaction. This phenomenon isknown as the Kinetic Isotope Effect. For example, if a C-H bond isbroken during a rate-determining step in a chemical reaction (i.e. thestep with the highest transition state energy), substitution of adeuterium for that hydrogen will cause a decrease in the reaction rateand the process will slow down. This phenomenon is known as theDeuterium Kinetic Isotope Effect (Foster et. al., Adv. Drug Res., 1985,14, 1-36; Kushner et. al., Can. J. Physiol. Pharmacol., 1999, 77,79-88).

Improvement of metabolism, pharmacokinetics, pharmacodynamics, andtoxicity profiles of pharmaceuticals by isotopic enrichment such asdeuteration has been demonstrated by the following examples: Lijinskyet. al., J. Nat. Cancer Inst., 1982, 69, 1127-1133; Gately et. al., J.Nucl. Med., 1986, 27, 388-394; Gordon et. al., Drug Metab. Dispos.,1987, 15, 589-594; Mangold et. al., Mutation Res., 1994, 308, 33-42;Zello et. al., Metabolism, 1994, 43, 487-491; Wade D., Chem. Biol.Interact., 1999, 117,191-637.

Preparation of the Compounds of Formula (I), (IA) or (IB)

It is understood that in the following description, combinations ofsubstituents and/or variables of the depicted formulae are permissibleonly if such contributions result in stable compounds.

It will also be appreciated by those skilled in the art that in theprocess described below the functional groups of intermediate compoundsmay need to be protected by suitable protecting groups. Such functionalgroups include hydroxy, amino, mercapto and carboxylic acid. Suitableprotecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl(e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl),tetrahydropyranyl, benzyl, and the like. Suitable protecting groups foramino, amidino and guanidino include t-butoxycarbonyl,benzyloxycarbonyl, and the like. Suitable protecting groups for mercaptoinclude —C(O)—R″ (where R″ is alkyl, aryl or arylalkyl),p-methoxybenzyl, trityl and the like. Suitable protecting groups forcarboxylic acid include alkyl, aryl or arylalkyl esters.

Protecting groups may be added or removed in accordance with standardtechniques, which are well-known to those skilled in the art and asdescribed herein.

The use of protecting groups is described in detail in Green, T. W. andP. G. M. Wutz, Protective Groups in Organic Synthesis (1999), 3rd Ed.,Wiley. The protecting group may also be a polymer resin such as a Wangresin or a 2-chlorotrityl-chloride resin.

It will also be appreciated by those skilled in the art, although suchprotected derivatives of compounds of this disclosure may not possesspharmacological activity as such, they may be administered to a mammaland thereafter metabolized in the body to form compounds of thedisclosure which are pharmacologically active. Such derivatives maytherefore be described as “prodrugs”. All prodrugs of compounds of thisdisclosure are included within the scope of the disclosure.

The following Reaction Schemes illustrate methods to make compounds ofthis disclosure. It is understood that one of those skilled in the artwould be able to make these compounds by similar methods or by methodsknown to one skilled in the art. In general, starting components may beobtained from sources such as Sigma Aldrich, Lancaster Synthesis, Inc.,Maybridge, Matrix Scientific, TCI, and Fluorochem USA, etc. orsynthesized according to sources known to those skilled in the art (see,e.g., Advanced Organic Chemistry: Reactions, Mechanisms, and Structure,5th edition (Wiley, December 2000)) or prepared as described in thisdisclosure.

As representative examples, compounds of formula (IA1), in which W is

(i.e., A is —O—, A¹ is —C(R⁵)═; A² is —N═) and R⁵ is hydrogen can besynthesized following the general procedure as described in ReactionScheme 1.

The starting materials for the above reaction scheme are commerciallyavailable or can be prepared according to methods known to one skilledin the art or by methods disclosed herein. In general, the compounds ofthe Formula (I) or (IA1) are prepared in the above reaction scheme asfollows:

The starting α-bromo ketone 101 is treated with hexamethylenetetramineunder Delépine reaction conditions to afford the α-amino ketone 102 as ahydrochloride salt. Under amide formation conditions,2-amino-5-bromonicotinic acid 103 reacts with compound 102 in thepresence of a coupling reagent, such as, but not limited to, EDCI toform compound 104. The oxazole compound 105 is obtained under acidcyclization conditions. This oxazole compound is coupled with the boronreagent 106 under the Suzuki coupling reaction conditions to afford thecompound of formula (IA1) where W is

and R⁵ is hydrogen.

Compounds of formula (IA2), in which W is

(i.e., A is —C(R⁵)═; A¹ is —O—, A² is —N═) and R⁵ is hydrogen can besynthesized following the general procedure as described in ReactionScheme 2.

The starting materials for the above reaction scheme are commerciallyavailable or can be prepared according to methods known to one skilledin the art or by methods disclosed herein. In general, the compounds ofthe Formula (IA2) are prepared in the above reaction scheme as follows:

The starting material, an appropriately substituted2-amino-5-bromonicotinic aldehyde 201 reacts with hydroxylaminehydrochloride salt under reflux to afford the nicotinic aldoximeintermediate 202. This oxime compound is then treated withN-chlorosuccinimide to generate the chlorinated oxime compound 203 whichis cyclized with acetylene compound 204 to afford the isoxazole compound205. This isoxazole compound is coupled with the boron reagent 206 underthe Suzuki coupling reaction conditions to afford the compound offormula (IA2).

Alternatively, compounds of formula (IA3), in which W is

(i.e., A is —O—, each of A¹ and A² is —C(R⁵)═) and each R⁵ is hydrogen,can be synthesized following the general procedure as described inReaction Scheme 3.

The starting materials for the above reaction scheme are commerciallyavailable or can be prepared according to methods known to one skilledin the art or by methods disclosed herein. In general, the compounds ofthe Formula (IA3) are prepared in the above reaction scheme as follows:

The starting α-ketoalkene 301 reacts with aldehyde compound 302 (e.g.,an appropriately substituted 2-amino-5-bromonicotinic aldehyde) underthe Stetter Reaction conditions in the presence of a thiazoliumcatalyst, such as, but not limited to,3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride, to afford1,4-dione compound 303, which is cyclized under the Paal-Knorr furansynthesis conditions to afford the furan compound 304. This furancompound is further coupled with the boron reagent 306 under the Suzukicoupling reaction conditions to afford the compound of formula (IA3).

In general, compounds of formula (IA4), in which W is

(i.e., A is —O—, each A¹ and A² is —N═) can be synthesized following thegeneral procedure as described in Reaction Scheme 4.

The starting materials for the above reaction scheme are commerciallyavailable or can be prepared according to methods known to one skilledin the art or by methods disclosed herein. In general, the compounds ofthe disclosure are prepared in the above reaction scheme as follows:

The starting carboxylic acid 401 reacts with hydrazide 402 in thepresence of a coupling reagent, such as, but not limited to, HATU and abase, such as, but not limited to, triethylamine to generate the1,2-diacylhydrazine compound 403. Cyclodehydration of compound 403 inthe presence of a dehydrating reagent, such as, but not limited to,triphenylphosphine/carbon tetrabromide to generate the 1,3,4-oxadiazole404. This oxadiazole compound is coupled with the boron reagent 406under the Suzuki coupling reaction conditions to afford the compound ofFormula (IA4).

Compounds of formula (IA5) of this disclosure in which W is

(i.e., A is —N═, A¹ is —N═, A² is —O—) can be synthesized following thegeneral procedure as described in Reaction Scheme 5.

The starting materials for the above reaction scheme are commerciallyavailable or can be prepared according to methods known to one skilledin the art or by methods disclosed herein. In general, the compounds ofthe disclosure are prepared in the above reaction scheme as follows:

Nitrile compound 501 is treated with hydroxylamine hydrochloride in thepresence of a base, such as, but not limited to, triethylamine underreflux to generate amidoxime compound 502. A condensation reaction ofthe amidoxime compound 602 with an appropriately substituted nicotinicacid 503 in the presence of a coupling agent, such as, but not limitedto, EDCI generates compound 504. Under reflux in the presence ofpyridine, compound 504 is cyclized to afford 1,2,4-oxadiazole compound505. This oxadiazole compound is coupled with a boron reagent 506 underthe Suzuki coupling reaction conditions to afford the compound offormula (IAS).

Compounds of Formula (IA6) of this disclosure in which W is

(i.e., A is —N═, A¹ is —O—, A² is —N═) can be synthesized following thegeneral procedure as described in Reaction Scheme 6.

The starting materials for the above reaction scheme are commerciallyavailable or can be prepared according to methods known to one skilledin the art or by methods disclosed herein. In general, the compounds ofthe disclosure are prepared in the above reaction scheme as follows:

Nitrile compound 601 is treated with hydroxylamine hydrochloride in thepresence of a base, such as, but not limited to, triethylamine underreflux to generate amidoxime compound 602. The condensation of amidoxime602 with carboxlic acid 303 in the presence of a coupling agent, suchas, but not limited to, EDCI generates compound 604. Under reflux in thepresence of pyridine, compound 604 is cyclized to afford1,2,4-oxadiazole compound 605. This oxadiazole compound is coupled withthe boron reagent 606 under the Suzuki coupling reaction conditions toafford the compound of formula (I) of the disclosure.

More specific details on synthetic techniques for compounds of Formula(I), (IA) and (IB) and their substructures are provided herein. Unlessotherwise provided, all reagents and reaction conditions employed insynthesis are known to those skilled in the art and are available fromordinary commercial sources.

PREPARATIONS Preparation 1 PREPARATION OF 2-AMINO-1-PHENYLETHANONEHYDROCHLORIDE

To a solution of 2-bromo-1-phenylethanone (5.00 g, 25.0 mmol) in 25 mLof chloroform was added a solution of hexamethylenetetramine (3.50 g,25.0 mmol) in 15 mL of chloroform dropwise. The resulting mixture wasstirred at ambient temperature for 1 hour to yield a white solid. Thewhite solid collected by filtration was dissolved in 50 mL of methanoland 10.0 mL of concentrated hydrochloroic acid was added. The mixturewas refluxed for 3 hours to afford white precipitates. The precipitateswere collected by filtration and washed with tetrahydrofuran to afford2-amino-1-phenylethanone hydrochloride as a white solid in 66% yield(2.80 g) which was used directly for the next step reaction withoutfurther purification. ¹H NMR (400 MHz, DMSO-d₆): δ 8.49 (br s, 3H),8.00-7.96 (m, 2H), 7.72-7.66 (m, 1H), 7.56-7.50 (m, 2H), 4.54 (s, 2H).

Preparation 1.1 PREPARATION OF 2-AMINO-1-(4-CHLOROPHENYL)ETHANONEHYDROCHLORIDE

Following the procedure as described in Preparation 1, making variationsusing 2-bromo-1-(4-chlorophenyl)ethanone to replace2-bromo-1-phenylethanone, 2-amino-1-(4-chlorophenyl)ethanonehydrochloride was obtained as a white solid in a quantitative yield. ¹HNMR (400 MHz, DMSO-d₆): δ 8.52 (br s, 3H), 8.02-7.97 (m, 2H), 7.65-7.60(m, 2H), 4.53 (s, 2H).

Preparation 1.2 PREPARATION OF 2-AMINO-1-(3-CHLOROPHENYL)ETHANONEHYDROCHLORIDE

Following the procedure as described in Preparation 1, making variationsusing 2-bromo-1-(3-chlorophenyl)ethanone to replace2-bromo-1-phenylethanone, 2-amino-1-(3-chlorophenyl)ethanonehydrochloride was obtained as a white solid in 96% yield. ¹H NMR (400MHz, DMSO-d₆): δ 8.54 (br s, 3H), 8.02-7.98 (m, 1H), 7.96-7.92 (m, 1H),7.78-7.74 (m, 1H), 7.62-7.56 (m, 1H), 4.57 (s, 2H).

Preparation 2 PREPARATION OF2-AMINO-5-BROMO-N-(2-OXO-2-PHENYLETHYL)NICOTINAMIDE

To a suspension of 2-amino-5-bromopyridine-3-carboxylic acid (0.43 g,2.00 mmol) and 2-amino-1-phenylethanone hydrochloride (0.51 g, 3.00mmol) in 40 mL of dichloromethane was added1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (1.19 g, 6.00 mmol). Themixture was stirred at ambient temperature for 3 hours. After removal ofthe solvent in vacuo, the residue was purified by column chromatographyeluted with 1:1 ethyl acetate:hexane to afford2-amino-5-bromo-N-(2-oxo-2-phenylethyl)nicotinamide as a yellow solid in72% yield (0.48 g). ¹H NMR (400 MHz, CDCl₃): δ 8.21 (d, J=2.0 Hz, 1H),8.13-8.02 (m, 2H), 8.03 (d, J=2.0 Hz, 1H), 7.70-7.65 (m, 1H), 7.58-7.52(m, 2H), 7.24 (t, J=4.4 Hz, 1H), 6.57 (br s, 2H), 4.91 (d, J=4.4 Hz,2H).

Preparation 2.1 PREPARATION OF2-AMINO-5-BROMO-N-(2-(4-CHLOROPHENYL)-2-OXOETHYL)NICOTINAMIDE

Following the procedure as described in Preparation 2, making variationsusing 2-amino-1-(4-chlorophenyl)ethanone hydrochloride to replace2-amino-1-phenyl-ethanone hydrochloride,2-amino-5-bromo-N-(2-(4-chlorophenyl)-2-oxoethyl)-nicotinamide wasobtained as a yellow solid in 55% yield. ¹H NMR (400 MHz, CDCl₃): δ 8.12(s, 1H), 8.11 (s, 1H), 7.90 (d, J=6.8 Hz, 2H), 7.80 (d, J=4.8 Hz, 1H),7.44 (d, J=6.8 Hz, 2H), 6.58 (br s, 2H), 4.77 (d, J=4.8 Hz, 2H).

Preparation 3 PREPARATION OF5-BROMO-3-(5-PHENYLOXAZOL-2-YL)PYRIDIN-2-AMINE

A mixture of 2-amino-5-bromo-N-(2-oxo-2-phenylethyl)nicotinamide (450mg, 1.35 mmol) in 10 mL of concentrated sulfuric acid was stirred atambient temperature for 18 hours. The mixture was mixed with 20 mL ofice cold water and neutralized with aqueous ammonia to yield yellowprecipitates. After suction filtration, the yellow precipitates werewashed with water to afford5-bromo-3-(5-phenyloxazol-2-yl)pyridin-2-amine as a yellowish solid in88% yield (375 mg). ¹H NMR (400 MHz, CD₃OD): δ 8.28 (s, 1H), 8.18 (s,1H), 7.74-7.70 (m, 2H), 7.54-7.34 (m, 4H), 6.85 (br s, 2H).

Preparation 3.1 PREPARATION OF5-BROMO-3-(5-(4-CHLOROPHENYL)OXAZOL-2-YL)PYRIDIN-2-AMINE

Following the procedure as described in Preparation 3, making variationsusing 2-amino-5-bromo-N-(2-(4-chlorophenyl)-2-oxoethyl)nicotinamide toreplace 2-amino-5-bromo-N-(2-oxo-2-phenylethyl)nicotinamide,5-bromo-3-(5-(4-chlorophenyl)-oxazol-2-yl)pyridin-2-amine was obtainedas a yellow solid in 86%. ¹H NMR (400 MHz, CDCl₃): δ 8.24 (s, 1H), 8.19(s, 1H), 7.65 (d, J=8.0 Hz, 2H), 7.50-7.38 (m, 3H), 6.75 (br s, 2H).

Preparation 4 PREPARATION OF5-BROMO-3-(5-(3-CHLOROPHENYL)OXAZOL-2-YL)PYRIDIN-2-AMINE

To a suspension of 2-amino-5-bromopyridine-3-carboxylic acid (1.75 g,8.09 mmol) and 2-amino-1-(3-chlorophenyl)ethanone hydrochloride (2.50 g,12.1 mmol) in 100 mL of dichloromethane was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (3.19 g, 16.2 mmol). Themixture was stirred at ambient temperature overnight to yield yellowprecipitates. After filtration, the yellow precipitates were washed withdichloromethane to afford a yellow solid which was mixed with 10 mL ofconcentrated sulfuric acid and was stirred at ambient temperature for 20hours. The reaction mixture was mixed with 40 mL of ice cold water andneutralized with ammonia solution to yield yellow precipitates. Aftersuction filtration, the yellow precipitates were washed with water toafford 5-bromo-3-(5-(3-chlorophenyl)oxazol-2-yl)pyridin-2-amine as anorange solid in 77% (2.00 g). ¹H NMR (400 MHz, CDCl₃): δ 8.27 (d, J=2.4Hz, 1H), 8.19 (d, J=2.4 Hz, 1H), 7.71 (s, 1H), 7.65-7.57 (m, 1H),7.55-7.45 (m, 1H), 7.45-7.33 (m, 2H), 6.78 (br s, 2H).

Preparation 5 PREPARATION OF5-BROMO-3-(5-PHENYLISOXAZOL-3-YL)PYRIDIN-2-AMINE

A. To a solution of 2-aminopyridine-3-carbaldehyde (10.1 g, 81.0 mmol)in acetonitrile (150 mL) was added N-bromosuccinimide (15.1 g, 84.0mmol). The resulting mixture was stirred at reflux for 2 hours. Aftercooled to room temperature, the reaction mixture was filtered. Thecollected solid was washed with methanol, and dried in vacuo to afford2-amino-5-bromopyridine-3-carbaldehyde as a brown solid in 79% yield(12.9 g). ¹H NMR (400 MHz, CDCl₃): δ 9.81 (s, 1H), 8.30 (d, J=2.4 Hz,1H), 7.89 (d, J=2.4 Hz, 1H), 6.78 (br s, 2H).

B. A mixture of 2-amino-5-bromopyridine-3-carbaldehyde (8.90 g, 44.3mmol), hydroxylamine hydrochloride (3.72 g, 53.1 mmol) and sodiumacetate (4.36 g, 53.1 mmol) in 95% ethanol (150 mL) was stirred underreflux for 3 hours. After cooled to room temperature, the reactionmixture was concentrated and the residue was re-dissolved in ethylacetate (500 mL), washed with brine (2×300 mL). The aqueous phase wasback-washed with ethyl acetate (2×250 mL). The combined organic layerwas washed with brine (2×250 mL), dried and filtered. The solvent of thefiltrate was removed in vacuo, and the residue was dried in vacuo toafford 2-amino-5-bromopyridine-3-carbaldehyde oxime as a yellow solid in90% yield (8.60 g). ¹H NMR (400 MHz, CDCl₃): δ 11.4 (s, 1H), 8.19 (s,1H), 7.98 (d, J=2.4 Hz, 1H), 7.77 (d, J=2.4 Hz, 1H), 7.10 (br s, 2H).

C. To a suspension of 2-amino-5-bromopyridine-3-carbaldehyde oxime (4.32g, 20.0 mmol) was added N-chlorosuccinimide (2.99 g, 22.0 mmol). Themixture was stirred at 50° C. overnight and then cooled to roomtemperature, and followed by the addition of dichloromethane (100 mL),phenylacetylene (2.24 mL, 20.0 mmol) and triethylamine (4.20 mL, 30.0mmol). The resulting mixture was stirred at room temperature overnight,then diluted with ethyl acetate (500 mL), washed with brine (4×300 mL).The aqueous phase was back-washed with ethyl acetate (1×300 mL). Thecombined organic layer was washed with brine (3×150 mL), dried andfiltered. The solvent of the filtrate was removed in vacuo and theresidue was purified by column chromatography eluted with hexanes:ethylacetate (from 10:1 to 5:1) to afford5-bromo-3-(5-phenylisoxazol-3-yl)pyridin-2-amine as a yellow solid in 6%yield (366 mg). ¹H NMR (400 MHz, CDCl₃): δ 8.19 (d, J=2.4 Hz, 1H), 7.89(d, J=2.4 Hz, 1H), 7.87-7.82 (m, 2H), 7.55-7.48 (m, 3H), 6.87 (s, 1H),6.40-6.25 (br s, 2H).

Preparation 6 PREPARATION OF5-BROMO-3-(5-PHENYLFURAN-2-YL)PYRIDIN-2-AMINE

A. A mixture of 3-chloro-1-phenylpropan-1-one (2.00 g, 11.9 mmol) andtriethylamine (1.44 g, 14.2 mmol) in chloroform was stirred at roomtemperature overnight. The reaction mixture was diluted withdichloromethane, washed with 0.1 M hydrochloric acid solution (2×20 mL)and brine (20 mL). The organic solution was dried over anhydrous sodiumsulfate and filtered. The filtrate was dried in vacuo to afford1-phenylprop-2-en-1-one as a yellow liquid in 91% yield (1.42 g). ¹H NMR(400 MHz, CDCl₃): δ 7.97-7.92 (m, 2H), 7.61-7.54 (m, 1H), 7.51-7.44 (m,2H), 7.16 (dd, J=17.2, 10.8 Hz, 1H), 6.44 (dd, J=17.2, 1.6 Hz, 1H), 5.93(dd, J=10.8, 1.6 Hz, 1H).

B. A mixture of 1-phenylprop-2-en-1-one (1.40 g, 10.6 mmol),2-amino-5-bromopyridine-3-carbaldehyde (1.70 g, 8.48 mmol) andtriethylamine in 5 mL of dioxane was heated at 100° C. for 10 minutes,followed by the addition of3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride (0.49 g, 1.59mmol) in 20 mL of dioxane dropwise in 0.5 hour. The resulting mixturewas heated at 100° C. overnight, then concentrated. The residue waspurified by column chromatography eluted with 10% ethyl acetate inhexane to afford1-(2-amino-5-bromopyridin-3-yl)-4-phenylbutane-1,4-dione as a yellowsolid in 13% yield (300 mg). ¹H NMR (400 MHz, CDCl₃): δ 8.25 (d, J=2.4Hz, 1H), 8.21 (d, J=2.4 Hz, 1H), 8.08-8.02 (m, 2H), 7.62-7.56 (m, 1H),7.52-7.46 (m, 2H), 3.47-3.36 (m, 4H).

C. A mixture of 1-(2-amino-5-bromopyridin-3-yl)-4-phenylbutane-1,4-dione(300 mg, 0.900 mmol) and p-toluenesulfonic acid (0.860 g, 4.50 mmol) in10 mL of toluene was heated at 100° C. for 2 hours, then concentrated.The residue was neutralized with saturated sodium bicarbonate, thenextracted with dichloromethane (3×20 mL). The organic solution was driedover anhydrous sodium sulfate and filtered. The solvent of the filtratewas removed in vacuo and the residue was purified by columnchromatography eluted with 20% ethyl acetate in hexane to afford5-bromo-3-(5-phenylfuran-2-yl)pyridin-2-amine as a yellow solid in 48%yield (136 mg). ¹H NMR (400 MHz, CDCl₃): δ 8.08 (d, J=2.4 Hz, 1H), 7.89(d, J=2.4 Hz, 1H), 7.73-7.68 (m, 2H), 7.47-7.41 (m, 2H), 7.35-7.28 (m,1H), 6.80 (d, J=3.6 Hz, 1H), 6.76 (d, J=3.6 Hz, 1H), 5.23 (br s, 2H).

Preparation 7 PREPARATION OF5-BROMO-3-(5-(PYRIDIN-3-YL)OXAZOL-2-YL)PYRIDIN-2-AMINE

A. To a solution of 1-(pyridin-3-yl)ethanone (10.0 g, 82.4 mmol) in 100mL of acetic acid was added 48% (w/v) hydrobromic acid in acetic acid(21.8 mL, 123.6 mmol), followed by the addition of bromine dropwise. Theresulting mixture was heated at 60° C. for 2 hours to yield whiteprecipitates. After filtration, the solid was washed with ether toafford a white solid which was mixed with 200 mL of acetonitrile andsodium diformylamide (16.9 g, 178 mmol) was added. The mixture washeated at 60° C. for 3 hours. After removal of solvent, the residue waspurified by column chromatography to affordN-formyl-N-(2-oxo-2-(pyridin-3-yl)ethyl)formamide as a yellowish wax in23% yield (1.6 g). ¹H NMR (400 MHz, CDCl₃): δ 9.23 (m, 1H), 9.05 (s,2H), 8.89-8.83 (m, 1H), 8.27-8.22 (m, 1H), 7.52-7.45 (m, 1H), 5.10 (s,2H).

B. To a solution of of N-formyl-N-(2-oxo-2-(pyridin-3-yl)ethyl)formamide(1.60 g, 8.33 mmol) in 150 mL of ethanol was added 10.0 mL ofconcentrated hydrochloric acid. The mixture was heated at 50° C.overnight to yield white precipitates which were collected by filtrationand washed with ice cold ethanol to afford2-amino-1-(pyridin-3-yl)ethanone hydrochloride as a white solid in 81%yield (1.17 g). ¹H NMR (400 MHz, DMSO-d₆): δ 9.25-9.22 (m, 1H),8.93-8.90 (m, 1H), 8.62-8.53 (br s, 3H), 8.63-8.49 (m, 1H), 7.78-7.75(m, 1H), 4.65-4.58 (m, 2H).

C. To a suspension of 2-amino-5-bromopyridine-3-carboxylic acid (0.566g, 2.60 mmol) and 2-amino-1-(pyridin-3-yl)ethanone hydrochloride (0.500g, 2.90 mmol) in 40 mL of dichloromethane was added HATU (1.97 g, 5.20mmol), followed by the addition of N,N-diisopropylethylamine (1.00 mL,5.80 mmol). The mixture was stirred at room temperature overnight toyield white precipitates. After filtration, the white precipitates werewashed with water to afford2-amino-5-bromo-N-(2-oxo-2-(pyridin-3-yl)ethyl)pyridine-3-carboxamide asa white solid in 69% yield (0.60 g). ¹H NMR (400 MHz, DMSO-d₆): δ9.17-9.14 (m, 1H), 9.00 (t, J=5.6 Hz, 1H), 8.82-8.78 (m, 1H), 8.35-8.28(m, 1H), 8.18-8.13 (m, 2H), 7.60-7.53 (m, 1H), 7.21 (br s, 2H), 4.74 (d,J=5.6 Hz, 2H).

D. To a cold (0° C.) suspension of2-amino-5-bromo-N-(2-oxo-2-(pyridin-3-yl)ethyl)pyridine-3-carboxamide(0.56 g, 1.67 mmol) in 25 mL of dichloromethane was added triethylamine(1.14 mL, 8.35 mmol), followed by the addition of triphenylphosphine(0.55 g, 2.09 mmol) and tetrabromomethane (0.69 g, 2.09 mmol). Theresulting mixture was stirred at room temperature for 5 hours. Afterremoval of solvent, the residue was purified by column chromatographyeluted with 3:2 ethyl acetate:dichloromethane to afford a yellow solidwhich was further purified by recrystallization in methanol to afford5-bromo-3-(5-(pyridin-3-yl)oxazol-2-yl)pyridin-2-amine as a light yellowsolid in 35% yield (0.185 g). ¹H NMR (400 MHz, CDCl₃): δ 9.02-8.98 (m,1H), 8.64-8.60 (m, 1H), 8.27 (d, J=2.4 Hz, 1H), 8.21 (d, J=2.4 Hz, 1H),8.04-7.99 (m, 1H), 7.56 (s, 1H), 7.44-7.40 (m, 1H), 6.75 (br s, 2H).

Preparation 8 PREPARATION OF 2-AMINO-5-BROMONICOTINOHYDRAZIDE

1. To a suspension of 2-aminonicotinic acid 1(13.8 g, 100 mmol) in 100mL of acetic acid was added bromine (5.70 mL, 110 mmol) dropwise over 20min. The mixture was stirred at ambient temperature for 1 h, evaporated,triturated with ether (50 mL). The solid was collected by filtration,washed with diethyl ether (2×20 mL) and dried in air. The product,2-amino-5-bromonicotinic acid hydrobromide, was obtained as a brownsolid in 93% yield (27.8 g). ¹H NMR (400 MHz, DMSO-d₆): δ 8.28 (d, J=2.4Hz, 1H), 8.15 (d, J=2.4 Hz, 1H), 5.00 (br s, 4H).

2. To a suspension of 2-amino-5-bromonicotinic acid hydrobromide (18.8g, 60.0 mmol) in 150 mL of methanol was added conc. sulfuric acid (6mL). The mixture was heated at 75° C. for 2 days, evaporated, dilutedwith water (100 mL), basified with solid sodium bicarbonate to pH 7-8,and extracted with ethyl acetate (3×100 mL). The extracts were washedwith brine (50 mL), dried over sodium sulfate and filtered. The filtratewas dried in vacuo and the residue was purified by flash chromatographyeluted with ethyl acetate/hexanes (¼) to afford methyl2-amino-5-bromonicotinate as a white solid in 36% yield (5.0 g). ¹H NMR(400 MHz, CDCl₃): δ 8.26 (d, J=2.8 Hz, 1H), 8.23 (d, J=2.8 Hz, 1H), 3.92(s, 3H).

3. To a solution of methyl 2-amino-5-bromonicotinate (4.95 g, 21.4 mmol)in tetrahydrofuran/methanol (30 mL/30 mL) was added 5.2 mL of hydrazinehydrate (NH₂NH.H₂O). The mixture was stirred at 75° C. for 18 h, andcooled. The solid was collected by filtration, washed with methanol(2×10 mL) and dried in air to afford 2-amino-5-bromonicotinohydrazide asa white solid (3.6 g). The filtrate was evaporated and purified bycolumn chromatography eluted with 5% methanol in dichloromethane toafford another 1.1 g of 2-amino-5-bromonicotinohydrazide as a whitesolid (total 4.7 g, 95%). ¹H NMR (400 MHz, DMSO-d₆): δ 9.74 (s, 1H),8.09 (d, J=2.4 Hz, 1H), 7.95 (d, J=2.4 Hz, 1H), 7.13 (s, 2H), 4.42 (s,2H).

Preparation 9 PREPARATION OF2-AMINO-5-BROMO-N′-(2,6-DICHLORO-3-FLUOROBENZOYL)NICOTINOHYDRAZIDE

To a cooled (0° C.) solution of 2-amino-5-bromonicotinohydrazide (0.71g, 3.08 mmol) in 18 mL of pyridine was added a solution of2,6-dichloro-3-fluorobenzoyl chloride (crude, 3.24 mmol, prepared from2,6-dichloro-3-fluorobenzoic acid (0.68 g, 3.24 mmol) with oxalylchloride) in dichloromethane (5 mL) dropwise. The mixture was warmed toambient temperature overnight and evaporated. The residue was purifiedby flash chromatography eluted with 3% methanol in dichloromethane toafford2-amino-5-bromo-N-(2,6-dichloro-3-fluorobenzoyl)nicotino-hydrazide as awhite solid in 26% yield (0.34 g). ¹H NMR (400 MHz, DMSO-d₆): δ 10.8 (s,1H), 10.7 (s, 1H), 8.24-8.18 (m, 2H), 7.62-7.52 (m, 2H), 7.24 (br s,2H).

Preparation 9.1 PREPARATION OF2-AMINO-N′-BENZOYL-5-BROMONICOTINOHYDRAZIDE

Following the procedure as described in Preparation 9, making variationsusing benzoyl chloride to replace 2,6-dichloro-3-fluorobenzoyl chlorideto react with 2-amino-5-bromonicotinohydrazide,2-amino-N′-benzoyl-5-bromonicotinohydrazide was obtained as a whitesolid in 72% yield. ¹H NMR (400 MHz, DMSO-d₆): δ 10.5 (s, 2H), 8.20-8.15(m, 2H), 7.89-7.85 (m, 2H), 7.59-7.46 (m, 3H), 7.22 (br s, 2H).

Preparation 9.2 PREPARATION OF SYNTHESIS OF2-AMINO-5-BROMO-N′-(4-(TERT-BUTYL)BENZOYL)NICOTINOHYDRAZIDE

Following the procedure as described in Preparation 9, making variationsusing 4-tert-butylbenzoyl chloride to replace2,6-dichloro-3-fluorobenzoyl chloride to react with2-amino-5-bromonicotinohydrazide,2-amino-5-bromo-N′-(4-(tert-butyl)benzoyl)-nicotinohydrazide wasobtained as a white solid in a quantitative yield. ¹H NMR (400 MHz,DMSO-d₆): δ 10.5 (s, 1H), 10.4 (s, 1H), 8.20-8.15 (m, 2H), 7.84-7.78 (m,2H), 7.52-7.46 (m, 2H), 7.22 (br s, 2H), 1.23 (s, 9H).

Preparation 9.3 PREPARATION OF2-AMINO-5-BROMO-N′-(2,5-DIFLUOROBENZOYL)NICOTINOHYDRAZIDE

Following the procedure as described in Preparation 9, making variationsusing 2,5-difluorobenzoyl chloride to replace2,6-dichloro-3-fluorobenzoyl chloride to react with2-amino-5-bromonicotinohydrazide,2-amino-5-bromo-N′-(2,5-difluorobenzoyl)-nicotinohydrazide was obtainedas a white solid in 94% yield. ¹H NMR (400 MHz, DMSO-d₆): δ 10.6 (s,1H), 10.4 (s, 1H), 8.19 (d, J=2.4 Hz, 1H), 8.15 (d, J=2.4 Hz, 1H),7.48-7.34 (m, 3H), 7.23 (br s, 2H).

Preparation 9.4 PREPARATION OF2-AMINO-5-BROMO-N′-(2,6-DICHLOROBENZOYL)NICOTINOHYDRAZIDE

Following the procedure as described in Preparation 9, making variationsusing 2,6-dichlorobenzoyl chloride to replace2,6-dichloro-3-fluorobenzoyl chloride to react with2-amino-5-bromonicotinohydrazide,2-amino-5-bromo-N′(2,6-dichlorobenzoyl)nicotinohydrazide was obtained asa white solid in 97% yield. ¹H NMR (400 MHz, DMSO-d₆): δ 10.7 (s, 1H),10.6 (s, 1H), 8.25-8.17 (m, 2H), 7.55-7.43 (m, 3H), 7.23 (br s, 2H).

Preparation 9.5 PREPARATION OF2-AMINO-5-BROMO-N′-(4-FLUOROBENZOYL)NICOTINOHYDRAZIDE

Following the procedure as described in Preparation 9, making variationsusing 4-fluorobenzoyl chloride to replace 2,6-dichloro-3-fluorobenzoylchloride to react with 2-amino-5-bromonicotinohydrazide,2-amino-5-bromo-N′-(4-fluorobenzoyl)nicotinehydrazide was obtained as awhite solid in 71% yield. ¹H NMR (400 MHz, DMSO-d₆): δ 10.5 (s, 2H),8.19 (d, J=2.4 Hz, 1H), 8.15 (d, J=2.4 Hz, 1H), 7.98-7.82 (m, 2H),7.36-7.28 (m, 2H), 7.21 (br s, 2H).

Preparation 9.6 PREPARATION OF2-AMINO-5-BROMO-N′-(CYCLOHEXANECARBONYL)NICOTINOHYDRAZIDE

Following the procedure as described in Preparation 9, making variationsusing cyclohexanecarbonyl chloride to replace2,6-dichloro-3-fluorobenzoyl chloride to react with2-amino-5-bromonicotinohydrazide,2-amino-5-bromo-N′-(cyclohexanecarbonyl)nicotinohydrazide was obtainedas a white solid in 16% yield. ¹H NMR (400 MHz, DMSO-d₆): δ 10.26 (br s,1H), 9.75 (br s, 1H), 8.16 (d, J=2.4 Hz, 1H), 8.08 (d, J=2.4 Hz, 1H),7.18 (br s, 2H), 2.26-2.17 (m, 1H), 1.75-1.66 (m, 4H), 1.64-1.56 (m,1H), 1.42-1.30 (m, 2H), 1.39-1.11 (m, 3H).

Preparation 10 PREPARATION OF5-BROMO-3-(5-(PYRIDIN-2-YL)-1,3,4-OXADIAZOL-2-YL)PYRIDIN-2-AMINE

Picolinic acid (149 mg, 99%, 1.20 mmol),2-amino-5-bromo-N′-nicotinoylnicotinohydrazide (231 mg, 1.00 mmol) and1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (576 mg, 1.50 mmol) were dissolved inN,N-dimethylformamide (3.0 mL), followed by the addition oftriethylamine (0.282 mL, 2.00 mmol). The resulting mixture was stirredat ambient temperature overnight, and then diluted with ethyl acetate(50 mL), washed with brine (2×50 mL), and dried over sodium sulfate.After filtration and removal of the solvent, the residue was dried undervacuum to afford a yellow solidN′-(2-amino-5-bromonicotinoyl)picolinohydrazide which was suspended indichloromethane (20 mL), followed by the addition of triethylamine(0.697 mL, 5.00 mmol), triphenylphosphine (331 mg, 1.25 mmol) and carbontetrachloride (419 mg, 99%, 1.25 mmol). The resulting mixture wasstirred at ambient temperature for 3 hrs, and then concentrated. Theresidue was treated with methanol (5.0 mL), and filtered. The solidcollected was washed with methanol and dried in vacuo to afford5-bromo-3-(5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine as ayellow solid in 59% yield (188 mg). ¹H NMR (400 MHz, CDCl₃): δ 8.84 (d,J=4.8 Hz, 1H), 8.40 (d, J=2.4 Hz, 1H), 8.33 (d, J=8.0 Hz, 1H), 8.28 (d,J=2.4 Hz, 1H), 7.98-7.90 (m, 1H), 7.68-7.64 (m, 1H), 6.90-6.70 (br s,2H).

Preparation 10.1 PREPARATION OF5-BROMO-3-(5-(PYRIDIN-3-YL)-1,3,4-OXADIAZOL-2-YL)PYRIDIN-2-AMINE

Following the procedure as described in Preparation 10, makingvariations using nicotinic acid to replace picolinic acid to react with2-amino-5-bromonicotinohydrazide,5-bromo-3-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine wasobtained as a yellow solid in 62% yield. ¹H NMR (400 MHz, CDCl₃): δ 9.38(s, 1H), 8.84 (d, J=4.8 Hz, 1H), 8.42 (d, J=4.8 Hz, 1H), 8.30 (s, 1H),8.22 (s, 1H), 7.53 (m, 1H), 6.85-6.55 (br s, 2H).

Preparation 10.2 PREPARATION OF5-BROMO-3-(5-(PYRAZIN-2-YL)-1,3,4-OXADIAZOL-2-YL)PYRIDIN-2-AMINE

Following the procedure as described in Preparation 10, makingvariations using pyrazine-2-carboxylic acid to replace picolinic acid toreact with 2-amino-5-bromonicotinohydrazide,5-bromo-3-(5-(pyrazin-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine wasobtained as a yellowish solid in 57% yield. ¹H NMR (400 MHz, CDCl₃): δ9.33 (s, 1H), 8.64-8.60 (m, 2H), 8.18 (d, J=2.4 Hz, 1H), 8.10 (d, J=2.4Hz, 1H), 7.20-7.05 (br s, 2H).

Preparation 10.3 PREPARATION OF3-(5-BENZYL-1,3,4-OXADIAZOL-2-YL)-5-BROMOPYRIDIN-2-AMINE

Following the procedure as described in Preparation 10, makingvariations using 2-phenylacetic acid to replace picolinic acid to reactwith 2-amino-5-bromonicotinohydrazide,3-(5-benzyl-1,3,4-oxadiazol-2-yl)-5-bromopyridin-2-amine was obtained asa white solid in 49% yield. ¹H NMR (400 MHz, CDCl₃): δ 8.21 (d, J=2.4Hz, 1H), 8.02 (d, J=2.4 Hz, 1H), 7.41-7.29 (m, 5H), 6.80-6.55 (br s,2H), 4.28 (s, 2H).

Preparation 10.4 PREPARATION OF5-BROMO-3-(5-(CYCLOPROPYLMETHYL)-1,3,4-OXADIAZOL-2-YL)PYRIDIN-2-AMINE

Following the procedure as described in Preparation 10, makingvariations using 2-cyclopropylacetic acid to replace picolinic acid toreact with 2-amino-5-bromonicotinohydrazide,5-bromo-3-(5-(cyclopropylmethyl)-1,3,4-oxadiazol-2-yl)-pyridin-2-aminewas obtained as a yellowish solid in 38% yield. ¹H NMR (400 MHz, CDCl₃):δ 8.24 (d, J=2.4 Hz, 1H), 8.10 (d, J=2.4 Hz, 1H), 6.85-6.60 (br s, 2H),2.85 (d, J=7.2 Hz, 2H), 1.27-1.16 (m, 1H), 0.71-0.65 (m, 2H), 0.39-0.36(m, 2H).

Preparation 10.5 PREPARATION OF5-BROMO-3-(5-(THIAZOL-2-YL)-1,3,4-OXADIAZOL-2-YL)PYRIDIN-2-AMINE

Following the procedure as described in Preparation 10, makingvariations using thiazole-2-carboxylic acid to replace picolinic acid toreact with 2-amino-5-bromonicotinohydrazide,5-bromo-3-(5-(thiazol-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine wasobtained as a yellow solid in 53% yield. ¹H NMR (400 MHz, CDCl₃): δ 7.90(d, J=2.4 Hz, 1H), 7.87 (d, J=2.4 Hz, 1H), 7.73 (d, J=3.2 Hz, 1H), 7.46(d, J=3.2 Hz, 1H), 7.00-6.85 (br s, 2H).

Preparation 10.6 PREPARATION OF5-BROMO-3-(5-(4-(TRIFLUOROMETHYL)THIAZOL-2-YL)-1,3,4-OXADIAZOL-2-YL)PYRIDIN-2-AMINE

Following the procedure as described in Preparation 10, makingvariations using 4-(trifluoromethyl)thiazole-2-carboxylic acid toreplace picolinic acid to react with 2-amino-5-bromonicotinohydrazide,5-bromo-3-(5-(4-(trifluoromethyl)-thiazol-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-aminewas obtained as a yellow solid in 35% yield. ¹H NMR (400 MHz, CDCl₃): δ8.37 (d, J=2.4 Hz, 1H), 8.32 (d, J=2.4 Hz, 1H), 8.07 (s, 1H), 6.85-6.55(br s, 2H).

Preparation 11 PREPARATION OF5-BROMO-3-(5-(2,6-DICHLORO-3-FLUOROPHENYL)-1,3,4-OXADIAZOL-2-YL)PYRIDIN-2-AMINE

To a suspension of2-amino-5-bromo-N′-(2,6-dichloro-3-fluorobenzoyl)-nicotinohydrazide(0.34 g, 0.81 mmol) in 20 mL of dichloromethane were added triethylamine(0.59 mL, 4.30 mmol), triphenylphosphine (0.28 g, 1.05 mmol) andtetrabromomethane (CBr₄) (0.35 g, 1.05 mmol). The mixture was stirredfor 18 h, and evaporated. The residue was purified by flashchromatography eluted with ethyl acetate/dichloromethane ( 1/20) toafford5-bromo-3-(5-(2,6-dichloro-3-fluorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-2-amineas a pale brown solid in 38% yield (0.125 g). ¹H NMR (400 MHz, DMSO-d₆):δ 8.32 (d, J=2.4 Hz, 1H), 8.20 (d, J=2.4 Hz, 1H), 7.88-7.81 (m, 2H),7.53 (br s, 2H).

Preparation 11.1 PREPARATION OF5-BROMO-3-(5-PHENYL-1,3,4-OXADIAZOL-2-YL)PYRIDIN-2-AMINE

Following the procedure as described in Preparation 11, makingvariations using 2-amino-N′-benzoyl-5-bromonicotinohydrazide to replace2-amino-5-bromo-N′-(2,6-dichloro-3-fluorobenzoyl)nicotinohydrazide,5-bromo-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyridin-2-amine was obtained asa white solid in 89% yield. ¹H NMR (400 MHz, DMSO-d₆): δ 8.44 (d, J=2.4Hz, 1H), 8.28 (d, J=2.4 Hz, 1H), 8.21-8.16 (m, 2H), 7.65-7.57 (m, 3H),7.48 (br s, 2H).

Preparation 11.2 PREPARATION OF5-BROMO-3-(5-(4-(TERT-BUTYL)PHENYL)-1,3,4-OXADIAZOL-2-YL)PYRIDIN-2-AMINE

Following the procedure as described in Preparation 11, makingvariations using2-amino-5-bromo-N44-(tert-butyl)benzoyl)nicotinohydrazide to replace2-amino-5-bromo-N′-(2,6-dichloro-3-fluorobenzoyl)nicotinohydrazide,5-bromo-3-(5-(4-(tert-butyl)-phenyl)-1,3,4-oxadiazol-2-yl)pyridin-2-aminewas obtained as a white solid in 82% yield. ¹H NMR (400 MHz, DMSO-d₆): δ8.42 (d, J=2.4 Hz, 1H), 8.27 (d, J=2.4 Hz, 1H), 8.12-8.08 (m, 2H),7.64-7.59 (m, 2H), 7.49 (br s, 2H), 1.31 (s, 9H).

Preparation 11.3 PREPARATION OF5-BROMO-3-(5-(2,5-DIFLUOROPHENYL)-1,3,4-OXADIAZOL-2-YL)PYRIDIN-2-AMINE

Following the procedure as described in Preparation 11, makingvariations using2-amino-5-bromo-N′-(2,5-difluorobenzoyl)nicotinohydrazide to replace2-amino-5-bromo-N′-(2,6-dichloro-3-fluorobenzoyl)nicotinohydrazide,5-bromo-3-(5-(2,5-difluoro-phenyl)-1,3,4-oxadiazol-2-yl)pyridin-2-aminewas obtained as a pale yellow solid in 87% yield. ¹H NMR (400 MHz,DMSO-d₆): δ 8.47 (d, J=2.4 Hz, 1H), 8.29 (d, J=2.4 Hz, 1H), 8.23-8.17(m, 1H), 7.59-7.53 (m, 2H), 7.49 (br s, 2H).

Preparation 11.4 PREPARATION OF5-BROMO-3-(5-(2,6-DICHLOROPHENYL)-1,3,4-OXADIAZOL-2-YL)PYRIDIN-2-AMINE

Following the procedure as described in Preparation 11, makingvariations using2-amino-5-bromo-N′-(2,6-dichlorobenzoyl)nicotinohydrazide to replace2-amino-5-bromo-N′-(2,6-dichloro-3-fluorobenzoyl)nicotinohydrazide,5-bromo-3-(5-(2,6-dichloro-phenyl)-1,3,4-oxadiazol-2-yl)pyridin-2-aminewas obtained as a white solid in 70% yield. ¹H NMR (400 MHz, DMSO-d₆): δ8.31 (d, J=2.4 Hz, 1H), 8.20 (d, J=2.4 Hz, 1H), 7.78-7.70 (m, 3H), 7.53(br s, 2H).

Preparation 11.5 PREPARATION OF5-BROMO-3-(5-(4-FLUOROPHENYL)-1,3,4-OXADIAZOL-2-YL)-PYRIDIN-2-AMINE

Following the procedure as described in Preparation 11, makingvariations using 2-amino-5-bromo-N′-(4-fluorobenzoyl)nicotinohydrazideto replace2-amino-5-bromo-N′-(2,6-dichloro-3-fluorobenzoyl)nicotinohydrazide,5-bromo-3-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine wasobtained as a pale yellow solid in 83% yield. ¹H NMR (400 MHz, DMSO-d₆):δ 8.47 (d, J=2.4 Hz, 1H), 8.28 (d, J=2.4 Hz, 1H), 8.27-8.23 (m, 2H),7.48 (br s, 2H), 7.48-7.42 (m, 2H).

Preparation 12 PREPARATION OF1-CYCLOHEXYL-4-(4,4,5,5-TETRAMETHYL-1,3,2-DIOXABOROLAN-2-YL)-1H-PYRAZOLE

1. To a cooled (0° C.) solution of cyclohexanol (2.50 g, 25.0 mmol) indichloromethane (50 mL) was added triethylamine (7.00 mL, 50.0 mmol),followed by the addition of methanesulfonyl chloride (2.91 mL, 37.5mmol). The mixture was stirred at ambient temperature for 20 h, dilutedwith dichloromethane (50 mL), washed with 1 N hydrochloroic acidsolution (20 mL), saturated sodium bicarbonate (30 mL), water (30 mL),brine (30 mL) and dried. The crude cyclohexyl methanesulfonate wasobtained as pale yellow oil after removal of the solvent (4.47 g, 100%yield). 1H NMR (300 MHz, CDCl3): δ 4.75-4.67 (m, 1H), 3.00 (s, 3H),2.04-1.95 (m, 2H), 1.83-1.74 (m, 2H), 1.70-1.59 (m, 2H), 1.57-1.49 (m,1H), 1.46-1.25 (m, 3H).

2. To a cooled (0° C.) solution of 4-bromo-1H-pyrazole (2.21 g, 15.0mmol) in dimethylformamide (25 mL) was added 60% sodium hydride (0.900g, 22.5 mmol) in portions. After 30 min, a solution of cyclohexylmethanesulfonate (2.84 g, 16.0 mmol) in dimethylformamide (4 mL) wasadded. The mixture was heated at 105° C. for 20 h. The volatiles wereremoved in vacuo and the residue was diluted with ethyl acetate (100mL), washed with water (2×20 mL), brine (20 mL) and dried. The residueafter removal of the solvents was purified by flash columnchromatography eluted with 5% ethyl acetate in hexanes to afford4-bromo-1-cyclohexyl-1H-pyrazole as a white solid in 33% yield (1.14 g).¹H NMR (400 MHz, CDCl₃): δ 7.45 (s, 1H), 7.44 (s, 1H), 4.13-4.05 (m,1H), 2.18-2.10 (m, 2H), 1.94-1.86 (m, 2H), 1.75-1.62 (m, 3H), 1.48-1.36(m, 2H), 1.31-1.19 (m, 1H).

3. To a solution of 4-bromo-1-cyclohexyl-1H-pyrazole (1.13 g, 4.95 mmol)in dimethyl sulfoxide (10 mL) was added potassium acetate (1.47 g, 15mmol), pinacol diboron (1.52 g, 6.00 mmol). The mixture was degassed for10 min, followed by the addition of PdCl₂(dppf) (0.300 g, 0.400 mmol).The mixture was degassed for another 10 min and heated at 90° C. for 20h, diluted with ethyl acetate (80 mL), washed with water (2×20 mL),brine (20 mL) and dried. The residue after removal of the solvents waspurified by flash column chromatography eluted with 10% ethyl acetate inhexanes to afford1-cyclohexyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleas a white solid in 20% yield (0.265 g). ¹H NMR (300 MHz, CDCl₃) δ 7.80(s, 1H), 7.75 (s, 1H), 4.21-4.11 (m, 1H), 2.21-2.14 (m, 2H), 1.94-1.85(m, 2H), 1.77-1.65 (m, 3H), 1.48-1.34 (m, 3H), 1.32 (s, 12H).

Preparation 13 PREPARATION OF N′-HYDROXYBENZAMIDINE

A mixture of benzonitrile (5.00 g, 48.5 mmol), hydroxylaminehydrochloride (8.42 g, 121 mmol) and triethylamine (30 mL) was refluxedin 30 mL of ethanol for 7 hours. After removal of solvent in vacuo, theresidue (white suspension) was mixed with water and extracted with ethylacetate (3×50 mL). The collected organic solution was dried over sodiumsulfate. N′-hydroxybenzamidine was obtained as a grey gum in 70% yield(4.60 g) after the removal of the solvent in vacuo. ¹H NMR (400 MHz,CDCl₃): δ 7.65-7.60 (m, 2H), 7.46-7.35 (m, 3H), 4.95 (br s, 2H).

Preparation 13.1 PREPARATION OF (Z)-2,6-DICHLORO-N′-HYDROXYBENZAMIDINE

Following the procedure as described in Preparation 13, makingvariations using 2,6-dichlorobenzonitrile to replace benzonitrile,(Z)-2,6-dichloro-N′-hydroxybenzamidine was obtained as a white solid in37% yield. ¹H NMR (400 MHz, DMSO-d₆): δ 9.38 (s, 1H), 7.48-7.45 (m, 2H),7.41-7.35 (m, 1H), 5.88 (br s, 2H).

Preparation 14 PREPARATION OFN′-(2-AMINO-5-BROMONICOTINOYL)OXY)BENZIMIDAMIDE

To a mixture of N′-hydroxybenzamidine (0.50 g, 3.68 mmol) and2-amino-5-bromopyridine-3-carboxylic acid (0.83 g, 4.05 mmol) in 30 mLof dichloromethane was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.45 g, 7.36 mmol). Theresulting mixture was stirred at ambient temperature overnight. Afterremoval of solvent in vacuo, the residue was purified by columnchromatography eluted with 5% methanol in dichloromethane to afford ayellow oil which was treated with dichloromethane and ethyl ether toafford N′-((2-amino-5-bromonicotinoyl)oxy)-benzimidamide as a yellowsolid in 32% yield (0.25 g). ¹H NMR (400 MHz, DMSO-d₆): δ 8.61 (d, J=2.4Hz, 1H), 8.25 (d, J=2.4 Hz, 1H), 7.74-7.70 (m, 2H), 7.52-7.42 (m, 3H),7.34 (br s, 2H), 7.04 (br s, 2H).

Preparation 14.1 PREPARATION OF(Z)-N′-(2-AMINO-5-BROMONICOTINOYL)OXY)-2,6-DICHLOROBENZIMIDAMIDE

Following the procedure as dedscribed in Preparation 14, makingvariations using (Z)-2,6-dichloro-N′-hydroxybenzamidine to replaceN′-hydroxybenzamidine to react with 2-amino-5-bromopyridine-3-carboxylicacid, (Z)-N′-((2-amino-5-bromonicotinoyl)oxy)-2,6-dichlorobenzimidamidewas obtained as a yellowish solid in 41% yield. ¹H NMR (400 MHz,DMSO-d₆): δ 8.67 (d, J=2.4 Hz, 1H), 8.25 (d, J=2.4 Hz, 1H), 7.56-7.46(m, 3H), 7.34 (br s, 4H).

Preparation 15 PREPARATION OF5-BROMO-3-(3-PHENYL-1,2,4-OXADIAZOL-5-YL)PYRIDIN-2-AMINE

A solution of N′-(2-amino-5-bromonicotinoyl)oxy)benzimidamide (0.30 g,0.90 mmol) in 5 mL of pyridine was refluxed for 3 hours. After cooling,precipitates were formed. After removal of pyridine by gravityfiltration, the precipitates were washed with water to afford5-bromo-3-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin-2-amine as a yellowishsolid in 92% yield (0.25 g). ¹H NMR (400 MHz, DMSO-d₆): δ 8.35 (d, J=2.4Hz, 1H), 8.32 (d, J=2.4 Hz, 1H), 8.15-8.10 (m, 2H), 7.66 (br s, 2H),7.60-7.54 (m, 3H).

Preparation 15.1 PREPARATION OF5-BROMO-3-(3-(2,6-DICHLOROPHENYL)-1,2,4-OXADIAZOL-5-YL)PYRIDIN-2-AMINE

Foloowing the procedure as described in Preparation 15, makingvariations usingN′-((2-amino-5-bromonicotinoyl)oxy)-2,6-dichlorobenzimidamide to replaceN′-(2-amino-5-bromonicotinoyl)oxy)benzimidamide,5-bromo-3-(3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl)pyridin-2-aminewas obtained as a yellowish solid in 67% yield. ¹H NMR (400 MHz, CDCl₃):δ 8.43 (d, J=2.4 Hz, 1H), 8.33 (d, J=2.0 Hz, 1H), 7.50-7.42 (m, 3H),6.80 (br s, 2H).

Preparation 16 PREPARATION OF(Z)-2-AMINO-5-BROMO-N′-HYDROXYNICOTINIMIDAMIDE

A solution of 2-amino-5-bromopyridine-3-carbonitrile (2.00 g, 10.1mmol), hydroxylamine hydrochloride (1.06 g, 15.3 mmol) and 24 mL oftriethylamine in 40 mL of ethanol was refluxed for 3 h. The resultingmixture was poured into ice cold water to afford a white solid. Thesolid was separated by filtration and washed with water. The filtratewas extracted with ethyl acetate and the organic layers were combined,dried over anhydrous sodium sulfate and filtered. The filtrate wasevaporate to afford a white solid which was combined with the whitesolid obtained earlier to afford(Z)-2-amino-N′-(benzoyloxy)-5-bromonicotinimidamide in quantitativeyield (2.30 g). ¹H NMR (400 MHz, DMSO-d₆): δ 9.95 (s, 1H), 7.96 (d,J=2.4 Hz, 1H), 7.89 (d, J=2.4 Hz, 1H), 7.20 (br s, 2H), 5.93 (s, 2H).

Preparation 17 PREPARATION OF5-BROMO-3-(5-PHENYL-1,2,4-OXADIAZOL-3-YL)PYRIDIN-2-AMINE

A. A mixture of benzoic acid (319 mg, 2.60 mmol),2-amino-5-bromo-N′-hydroxypyridine-3-carboxamidine (400 mg, 1.73 mmol)and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (627 mg, 3.24 mmol) indichloromethane (10 mL) was stirred at ambient temperature for 5 hoursand a white solid was precipitated. The solid was collected byfiltration, washed with dichloromethane, and dried in vacuo to afford(Z)-2-amino-N′-(benzoyloxy)-5-bromonicotinimidamide as a white solid in73% yield (422 mg). ¹H NMR (400 MHz, DMSO-d₆): δ 8.18 (dd, J=8.0, 1.2Hz, 2H), 8.10 (d, J=2.4 Hz, 1H), 8.00 (d, J=2.4 Hz, 1H), 7.66 (t, J=8.0Hz, 1H), 7.52 (t, J=8.0 Hz, 2H), 7.29 (br s, 2H), 7.04 (br s, 2H).

B. A suspension of (Z)-2-amino-N′-(benzoyloxy)-5-bromo-nicotinimidamide(405 mg, 1.21 mmol) in pyridine (6.0 mL, 77.0 mmol) was stirred at110-115° C. overnight. After cooled to ambient temperature, the reactionmixture was concentrated under high vacuum. The residue was azeotropedwith toluene (4×10 mL), and dried under vacuum for 30 minutes. The driedresidue was treated with methanol (10 mL), and a precipitate wasobtained. The precipitate was collected by filtration, and washed withmethanol (˜20 mL), and dried under vacuum to afford5-bromo-3-(5-phenyl-1,2,4-oxadiazol-3-yl)pyridin-2-amine as a yellowsolid (285 mg, 74%). ¹H NMR (400 MHz, CDCl₃): δ 8.56 (d, J=2.4 Hz, 1H),8.27 (d, J=2.4 Hz, 1H), 8.25-8.20 (m, 2H), 7.68-7.63 (m, 1H), 7.62-7.56(m, 2H), 6.30-6.17 (br s, 2H).

Preparation 18 PREPARATION OF5-BROMO-3-(5-(2,5-DICHLOROPHENYL)-1,2,4-OXADIAZOL-3-YL)PYRIDIN-2-AMINE

A. To a solution of 2-amino-5-bromo-N′-hydroxypyridine-3-carboxamidine(74 mg, 0.344 mmol) and 2,5-dichlorobenzoic acid (72 mg, 0.378 mmol) in5 mL of dichloromethane was added1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (98 mg, 0.516 mmol) and 1mL of N,N-dimethylformamide. The mixture was stirred at ambienttemperature overnight, followed by the addition of water to quench thereaction. The resulting mixture was extracted with dichloromethane (2×10mL). The combined organic solution was dried over anhydrous sodiumsulfate. After filtration and removal of solvent, the residue waspurified by flash column chromatography to afford(Z)-2-amino-5-bromo-N′-(2,5-dichlorobenzoyl)oxy)-nicotinimidamide as awhite solid in 72% yield (96 mg). ¹H NMR (400 MHz, DMSO-d₆): δ 8.12 (d,J=2.4 Hz, 1H), 8.11 (d, J=2.4 Hz, 1H), 7.97 (d, J=2.4 Hz, 1H), 7.65 (dd,J=8.0, 2.4 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.19 (br s, 2H), 7.08 (br s,2H).

B. A solution of(Z)-2-amino-5-bromo-N′-(2,5-dichlorobenzoyl)oxy)-nicotinimidamide (170mg, 0.463 mmol) in 5 mL of pyridine was refluxed for 2 h. The reactionmixture was cooled to room temperature and pyridine was removed invacuo. The resulting white solid was washed with water and collected byfiltration. The collected white solid was washed with a mixture of ethylacetate:dichloromethane (1:10) to remove the remaining starting materialto afford pure5-bromo-3-(5-(2,5-dichlorophenyl)-1,2,4-oxadiazol-3-yl)pyridin-2-amineas a yellow solid in 34% yield (60 mg). ¹H NMR (400 MHz, DMSO-d₆): 88.35(d, J=2.4 Hz, 1H), 8.31-8.28 (m, 2H), 7.82-7.77 (m, 2H), 7.12 (br s,2H).

Preparation 19 PREPARATION OF TERT-BUTYL4-(4-(4,4,5,5-TETRAMETHYL-1,3,2-DIOXABOROLAN-2-YL)-1H-PYRAZOL-1-YL)PIPERIDINE-1-CARBOXYLATE

A. To a cold solution (0° C.) of tert-butyl4-hydroxypiperidine-1-carboxylate (175 g, 0.87 mol) in 750 mL ofdichloromethane was added triethylamine (237 mL, 1.74 mol) dropwise,followed by the addition of mesyl chloride (101 mL, 1.31 mol) dropwise.The resulting mixture was stirred at room temperature for 2 hours, thendiluted with 400 mL of dichloromethane and washed with saturated sodiumbicarbonate (2×750 mL), water (1×600 mL) and brine (1×600 mL). Theorganic solution was dried over anhydrous sodium sulfate, and filtered.Removal of the solvent afforded tert-butyl4-((methylsulfonyl)oxy)piperidine-1-carboxylate as a yellow solid in96.8% yield (235 g). ¹H NMR (400 MHz, CDCl₃) δ 4.90-4.82 (m, 1H),3.73-3.64 (m, 2H), 3.34-3.25 (m, 2H), 3.03 (s, 3H), 2.00-1.92 (m, 2H),1.88-1.75 (m, 2H), 1.44 (s, 9H).

B. To a cold solution (0° C.) of 4-bromo-1H-pyrazole (14.9 g, 0.10 mol)in 80 mL of dichloromethane was added sodium hydride (8.13 g, 0.20 mol)portion wise. The mixture was stirred at 0° C. for 1 hour, followed bythe addition of a solution of tert-butyl4-((methylsulfonyl)oxy)piperidine-1-carboxylate (34.0 g, 0.12 mol) in 30ml, of N,N-dimethylformamide. The resulting mixture was heated at 110°C. overnight. Purification by column chromatography afforded tert-butyl4-(4-bromo-1H-pyrazol-1-yl)piperidine-1-carboxylate as a yellow oil in58% yield (19.5 g). ¹H NMR (400 MHz, CDCl₃) δ 7.48 (s, 1H), 7.44 (s 1H),4.35-4.20 (m, 3H), 2.95-2.85 (m, 2H), 2.15-2.05 (m, 2H), 1.92-1.81 (m,2H), 1.48 (s, 9H).

C. A mixture of tert-butyl4-(4-bromo-1H-pyrazol-1-yl)piperidine-1-carboxylate (20.0 g, 0.61 mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(30.8 g, 0.12 mmol) and potassium acetate (17.8 g, 0.18 mol) in 50 mL ofdimethyl sulfoxide was purged with nitrogen gas for 10 min. After theaddition of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(3.55 g, 4.85 mmol), the mixture was purged with nitrogen gas foranother 10 minutes, heated at 80° C. overnight under nitrogen atmosphereand filtered through celite and washed with ethyl acetate. The filtratewas extracted with ethyl acetate (2×200 mL). The organic layer was driedover anhydrous sodium sulfate. After filtration and removal of thesolvent, the residue was purified by column chromatograph eluted withhexane to afford an oil which was recrystallized from hexane to affordtert-butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylateas a white solid in 44% yield (10 g). ¹H NMR (400 MHz, CDCl₃) δ 7.79 (s,1H), 7.72 (s, 1H), 4.32-4.13 (m, 3H), 2.95-2.80 (m, 2H), 2.15-2.05 (m,2H), 1.93-1.82 (m, 2H), 1.47 (s, 9H), 1.31 (s, 12H).

Preparation 20 PREPARATION OF5-BROMO-3-(5-CYCLOHEXYL-1,3,4-OXADIAZOL-2-YL)PYRIDIN-2-AMINE

To a suspension of2-amino-5-bromo-N′-(cyclohexanecarbonyl)-nicotinohydrazide (0.20 g, 0.59mmol) in 15 mL of dichloromethane was added triethylamine (0.40 mL, 2.93mmol) and acetic anhydride (13 μL, 0.14 mmol), followed by the additionof triphenylphosphine (0.19 g, 0.73 mmol) and tetrabromomethane (0.24 g,0.73 mmol). The resulting mixture was stirred at room temperature for 2hours.

After removal of the solvent in vacuo, the residue was purified bycolumn chromatography eluted with 1:1 ethyl acetate:hexane to afford5-bromo-3-(5-cyclohexyl-1,3,4-oxadiazol-2-yl)pyridin-2-amine as a whitesolid in 77% yield (0.14 g). ¹H NMR (400 MHz, CDCl₃): δ 8.23 (d, J=2.4Hz, 1H), 8.07 (d, J=2.4 Hz, 1H), 6.61 (br s, 2H), 3.04-2.95 (m, 1H),2.20-2.10 (m, 2H), 1.94-1.84 (m, 2H), 1.80-1.60 (m, 3H), 1.50-1.30 (m,3H).

Preparation 21 PREPARATION OF TERT-BUTYL4-(3-(4,4,5,5-TETRAMETHYL-1,3,2-DIOXABOROLAN-2-YL)-1H-PYRROL-1-YL)PIPERIDINE-1-CARBOXYLATE

A. To an ice-cold solution of pyrrole (611 mg, 9.11 mmol) in 6 mL ofN,N-dimethylformamide was slowly added sodium hydride (364 mg, 9.11mmol, 60% in mineral oil). After stirred at room temperature for 1 hour,the resulting mixture was cooled to 0° C., followed by the addition of1-(tert-butoxycarbonyl)piperidin-4-yl methanesulfonate slowly. Themixture was then heated up to 110° C. and stirred overnight. Afterremoval of the solvent in vacuo, the residue was purified by columnchromatography eluted with 20% ethyl acetate in hexane to affordtert-butyl 4-(1H-pyrrol-1-yl)piperidine-1-carboxylate as a colorless oilin 21% yield (317 mg). ¹H NMR (400 MHz, CDCl₃): δ 6.75-6.71 (m, 2H),6.18-6.15 (m, 2H), 4.32-4.20 (m, 2H), 4.02-3.93 (m, 1H), 2.90-2.76 (m,2H), 2.07-2.03 (m, 2H), 1.89-1.78 (m, 2H), 1.48 (s, 9H).

B. To a solution of tert-butyl4-(1H-pyrrol-1-yl)piperidine-1-carboxylate (1.03 g, 3.72 mmol) in 30 mLof anhydrous tetrahydrofuran at −78° C. was added phosphorus tribromide(60 mg, 0.220 mmol) and N-bromosuccinimide (663 mg, 3.72 mmol) insequence. The mixture was stirred at −78° C. for 1 hour, and it was leftin the freezer (−15° C.) overnight. A white solid was precipitated afterthe addition of triethylamine (0.42 g, 1 equiv) and hexanes (40 mL) tothe mixture. The suspension was filtered through neutral aluminium oxidepad and dried over sodium sulfate. The removal of the solvent of thefiltrate afforded tert-butyl4-(3-bromo-1H-pyrrol-1-yl)piperidine-1-carboxylate (1.23 g) as yellowishoil which was used for the next step reaction without furtherpurification. ¹H NMR (400 MHz, CDCl₃): δ 6.71-6.69 (m, 1H), 6.63-6.61(m, 1H), 6.16-6.13 (m, 1H), 4.35-4.20 (m, 2H), 3.95-3.85 (m, 1H),2.89-2.76 (m, 2H), 2.06-1.98 (m, 2H), 1.89-1.76 (m, 2H), 1.47 (s, 9H).

C. A solution of tert-butyl4-(3-bromo-1H-pyrrol-1-yl)piperidine-1-carboxylate (1.23 g, 3.7 mmol),bis(pinacolato)diboron (1.90 g, 7.4 mmol) and potassium acetate (1.09 g,11.1 mmol) in 20 mL of dioxane in a sealed tube was degassed withnitrogen gas for 10 min, followed by the addition of1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (270 mg,0.37 mmol). The mixture was degassed for another 10 min. The tube wassealed and heated at 80° C. overnight. The resulting solution was washedwith water and extracted with ethyl acetate. Organic layers werecombined and evaporated and the residue was purified by columnchromatography eluted with 15% ethyl acetate in hexanes to affordtert-butyl4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrol-1-yl)piperidine-1-carboxylateas colorless oil in 14% yield (70 mg). ¹H NMR (400 MHz, CDCl₃): δ7.19-7.17 (m, 1H), 6.76-6.74 (m, 1H), 6.51-6.49 (m, 1H), 4.28-4.19 (m,2H), 4.02-3.92 (m, 1H), 2.86-2.78 (m, 2H), 2.04-2.01 (m, 2H), 1.88-1.78(m, 2H), 1.48 (s, 9H), 1.32 (s, 12H).

Preparation 22 PREPARATION OF1-(TETRAHYDRO-2H-PYRAN-4-YL)-4-(4,4,5,5-TETRAMETHYL-1,3,2-DIOXABOROLAN-2-YL)-1H-PYRAZOLE

A. To a cooled (0° C.) solution of tetrahydro-2H-pyran-4-ol (5.00 g,49.0 mmol) in dichloromethane (85 mL) was added triethylamine (5.95 mL,58.8 mmol), followed by the addition of methanesulfonyl chloride (6.74mL, 58.8 mmol). The mixture was stirred at room temperature overnight,diluted with dichloromethane (85 mL), then sequentially washed with 0.5N hydrochloric acid solution (40 mL), saturated sodium bicarbonate (50mL), water (50 mL), brine (50 mL), dried over anhydrous sodium sulfateand filtered. The filtrate was evaporated to afford the crude producttetrahydro-2H-pyran-4-ylmethanesulfonate (8.6 g, 97.4%) as a pale yellowsolid. ¹H NMR (400 Hz, CDCl₃) δ 4.95-4.85 (m, 1H), 3.97-3.90 (m, 2H),3.57-3.51 (m, 2H), 3.04 (s, 3H), 2.08-2.02 (m, 2H), 1.93-1.84 (m, 2H).B. To a cooled (0° C.) solution of 4-bromo-1H-pyrazole (3.00 g, 20.4mmol) in N,N-dimethylformamide (10 mL) was added 60% sodium hydride(0.90 g, 22.5 mmol) in portions, followed by the addition of a solutionof tetrahydro-2H-pyran-4-yl methanesulfonate (5.52 g, 30.6 mmol) inN,N-dimethylformamide (10 mL) 30 minutes later. The mixture was heatedat 110° C. overnight, cooled to room temperature and mixed with water(50 mL). The precipitates obtained were collected by filtration, washedwith water and dried to afford4-bromo-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole (2.90 g, 62%) as abrown solid. ¹H NMR (400 Hz, CDCl₃) δ 7.47 (s, 1H), 7.46 (s, 1H),4.35-4.30 (m, 1H), 4.12-4.08 (m, 2H), 3.55-3.48 (m, 2H), 2.15-2.00 (m,4H).

C. To a solution of 4-bromo-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole(2.90 g, 12.6 mmol) in dimethyl sulfoxide (25 mL) was added potassiumacetate (4.94 g, 50.4 mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(6.40 g, 25.2 mmol). The mixture was degassed for 10 min, and then[1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II) (0.922 g,1.26 mmol) was added. The mixture was degassed for another 10 minutesand heated at 90° C. overnight, diluted with ethyl acetate (80 mL),washed with water (2×20 mL), brine (20 mL), dried and filtered. Thesolvent of the filtrate was removed and the residue was purified byflash column chromatography eluted with 20% ethyl acetate in hexanes toafford1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.66 g, 19%) as a white solid. ¹H NMR (400 Hz, CDCl₃) δ 7.81 (s, 1H),7.76 (s, 1H), 4.42-4.32 (m, 1H), 4.14-4.06 (m, 2H), 3.58-3.50 (m, 2H),2.16-1.98 (m, 4H), 1.32 (s, 12H).

EXAMPLES Example 1 SYNTHESIS OF TERT-BUTYL4-(4-(6-AMINO-5-(5-PHENYL)-1,3,4-OXADIAZOL-2-YL)PYRIDIN-3-YL)-1H-PYRAZOL-1-YL)PIPERIDINE-1-CARBOXYLATE

To a solution of5-bromo-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyridin-2-amine (0.112 g, 0.353mmol) in dimethyl sulfoxide (5 mL) were added tert-butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(0.160 g, 0.424 mmol), potassium acetate (0.140 g, 1.40 mmol) andPdCl₂(dppf) (26.0 mg, 0.035 mmol). The mixture was degassed withnitrogen gas for 5 min, evaporated, heated at 100° C. for 20 h, cooled,diluted with 50 mL of ethyl acetate, washed with water (10 mL), andbrine (10 mL). The organic phase was dried in vacuo and the residue waspurified by flash chromatography eluted with 60% ethyl acetate inhexanes to afford the title compound as a pale brown solid in 24% yield(42 mg). ¹H NMR (400 MHz, CDCl₃): δ 8.40 (d, J=2.0 Hz, 1H), 8.19-8.15(m, 3H), 7.78 (d, J=0.8 Hz, 1H), 7.68 (d, J=0.8 Hz, 1H), 7.62-7.55 (m,3H), 6.63 (br s, 2H), 4.38-4.23 (m, 3H), 3.00-2.87 (m, 2H), 2.23-2.16(m, 2H), 2.06-1.83 (m, 2H), 1.50 (s, 9H).

The table below shows additional examples of compounds of Formula (IA4)that were prepared according to the above process.

Ex. No. Chemical Name Starting Material and Yield Characterization Data1.1 tert-butyl 4-(4-(6- 5-bromo-3-(5-(2,6-dichloro- ¹H NMR (400 MHz,CDCl₃): δ 8.42 amino-5-(5-(2,6- 3-fluorophenyl)-1,3,4- (d, J = 2.4 Hz,1H), 8.10 (d, J = 2.4 dichloro-3- oxadiazol-2-yl)pyridin-2- Hz, 1H),7.73 (d, J = 0.8 Hz, 1H), fluorophenyl)-1,3,4- amine and tert-butyl4-(4- 7.64 (d, J = 0.8 Hz, 1H), 7.52-7.48 oxadiazol-2-(4,4,5,5-tetramethyl-1,3,2- (m, 1H), 7.40-7.36 (m, 1H), 6.62 (bryl)pyridin-3-yl)-1H- dioxaborolan-2-yl)-1H- s, 2H), 4.35-4.22 (m, 3H),2.96-2.84 pyrazol-1- pyrazol-1-yl)piperidine-1- (m, 2H), 2.18-2.12 (m,2H), 1.98- yl)piperidine-1- carboxylate; 16% 1.91 (m, 2H), 1.46 (s, 9H).carboxylate 1.2 tert-butyl 4-(4-(5-(5- 3-(5-(4-tert-butylphenyl)- ¹H NMR(400 MHz, CDCl₃): δ 8.39 (4-tert-butylphenyl)- 1,3,4-oxadiazol-2-yl)-5-(d, J = 2.4 Hz, 1H), 8.15 (d, J = 2.4 1,3,4-oxadiazol-2-bromopyridin-2-amine and Hz, 1H), 8.11-8.07 (m, 2H), 7.78 (d,yl)-6-aminopyridin- tert-butyl 4-(4-(4,4,5,5- J = 0.8 Hz, 1H), 7.67 (d,J = 0.8 Hz, 3-yl)-1H-pyrazol-1- tetramethyl-1,3,2- 1H), 7.60-7.56 (m,2H), 6.61 (br s, yl)piperidine-1- dioxaborolan-2-yl)-1H- 2H), 4.38-4.20(m, 3H), 2.98-2.86 carboxylate pyrazol-1-yl)piperidine-1- (m, 2H),2.24-2.16 (m, 2H), 2.04- carboxylate; 22% 1.83 (m, 2H), 1.48 (s, 9H),1.38 (s, 9H). 1.3 tert-butyl 4-(4-(6- 5-bromo-3-(5-(2,5- ¹H NMR (400MHz, CDCl₃): δ 8.41 amino-5-(5-(2,5- difluorophenyl)-1,3,4- (d, J = 2.4Hz, 1H), 8.15 (d, J = 2.4 difluorophenyl)- oxadiazol-2-yl)pyridin-2- Hz,1H), 7.90-7.84 (m, 1H), 7.77 (d, 1,3,4-oxadiazol-2- amine and tert-butyl4-(4- J = 0.8 Hz, 1H), 7.66 (d, J = 0.8 Hz, yl)pyridin-3-yl)-1H-(4,4,5,5-tetramethyl-1,3,2- 1H), 7.30-7.26 (m, 2H), 6.60 (br s,pyrazol-1- dioxaborolan-2-yl)-1H- 2H), 4.36-4.22 (m, 3H), 2.98-2.86yl)piperidine-1- pyrazol-1-yl)piperidine-1- (m, 2H), 2.24-2.16 (m, 2H),2.03- carboxylate carboxylate; 18% 1.83 (m, 2H), 1.48 (s, 9H). 1.4tert-butyl 4-(4-(6- 5-bromo-3-(5-(2,6- ¹H NMR (400 MHz, CDCl₃): δ 8.42amino-5-(5-(2,6- dichlorophenyl)-1,3,4- (d, J = 2.4 Hz, 1H), 8.12 (d, J= 2.4 dichlorophenyl)- oxadiazol-2-yl)-pyridin-2- Hz, 1H), 7.74 (d, J =0.8 Hz, 1H), 1,3,4-oxadiazol-2- amine and tert-butyl 4-(4- 7.65 (d, J =0.8 Hz, 1H), 7.52-7.49 yl)pyridin-3-yl)-1H- (4,4,5,5-tetramethyl-1,3,2-(m, 3H), 6.63 (br s, 2H), 4.36-4.18 pyrazol-1- dioxaborolan-2-yl)-1H-(m, 3H), 2.96-2.84 (m, 2H), 2.20- yl)piperidine-1-pyrazol-1-yl)piperidine-1- 2.13 (m, 2H), 2.02-1.88 (m, 2H), carboxylatecarboxylate; 34% 1.48 (s, 9H). 1.5 tert-butyl 4-(4-(6- 5-bromo-3-(5-(4-¹H NMR (400 MHz, CDCl₃): δ 8.40 amino-5-(5-(4- fluorophenyl)-1,3,4- (d,J = 2.4 Hz, 1H), 8.21-8.15 (m, fluorophenyl)-1,3,4-oxadiazol-2-yl)-pyridin-2- 2H), 8.14 (d, J = 2.4 Hz, 1H), 7.78oxadiazol-2- amine and tert-butyl 4-(4- (d, J = 0.8 Hz, 1H), 7.67 (d, J= 0.8 yl)pyridin-3-yl)-1H- (4,4,5,5-tetramethyl-1,3,2- Hz, 1H),7.30-7.24 (m, 2H), 6.60 (br pyrazol-1- dioxaborolan-2-yl)-1H- s, 2H),4.39-4.23 (m, 3H), 2.98-2.87 yl)piperidine-1- pyrazol-1-yl)piperidine-1-(m, 2H), 2.24-2.16 (m, 2H), 2.04- carboxylate carboxylate; 35% 1.83 (m,2H), 1.48 (s, 9H). 1.6 3-(5-(2,6- 5-bromo-3-(5-(2,6- ¹H NMR (400 MHz,DMSO-d₆): δ dichlorophenyl)- dichlorophenyl)-1,3,4- 12.9 (br s, 1H),8.58-8.55 (m, 1H), 1,3,4-oxadiazol-2- oxadiazol-2-yl)-pyridin-2-8.24-8.21 (m, 1H), 8.20 (s, 1H), 7.92 yl)-5-(1H-pyrazol-4- amine andpyrazole-4- (s, 1H), 7.79-7.71 (m, 2H), 7.32 (br yl)pyridin-2-amineboronic acid pinacol ester; s, 2H); MS (ES+): m/z 373.2, 374.2 12% and375.2 (M + 1). 1.7 3-(5-phenyl-1,3,4- pyrazole-4-boronic acid ¹H NMR(400 MHz, DMSO-d₆): δ oxadiazol-2-yl)-5- pinacol ester and 5-bromo- 12.9(br s, 1H), 8.53 (d, J = 2.4 Hz, (1H-pyrazol-4- 3-(5-phenyl-1,3,4- 1H),8.40 (d, J = 2.4 Hz, 1H), 8.26- yl)pyridin-2-amineoxadiazol-2-yl)pyridin-2- 8.19 (m, 3H), 7.99 (s, 1H), 7.67-7.59 amine;21% (m, 3H), 7.26 (br s, 2H); MS (ES+): m/z 305.3 (M + 1). 1.83-(5-(4-tert- 5-bromo-3-(5-(4-(tert- ¹H NMR (400 MHz, DMSO-d₆): δbutylphenyl)-1,3,4- butyl)phenyl)-1,3,4- 8.52 (d, J = 2.4 Hz, 1H), 8.37(d, J = oxadiazol-2-yl)-5- oxadiazol-2-yl)pyridin-2- 2.4 Hz, 1H), 8.22(s, 1H), 8.14-8.10 (1H-pyrazol-4- amine and pyrazole-4- (m, 2H), 7.97(s, 1H), 7.64-7.60 (m, yl)pyridin-2-amine boronic acid pinacol ester;2H), 7.25 (br s, 2H), 1.33 (s, 9H). 21% MS (ES+): m/z 361.3 (M + 1). 1.93-(5-(2,5- 5-bromo-3-(5-(2,5- ¹H NMR (400 MHz, DMSO-d₆): δdifluorophenyl)- difluorophenyl)-1,3,4- 8.54 (d, J = 2.4 Hz, 1H), 8.38(d, J = 1,3,4-oxadiazol-2- oxadiazol-2-yl)-pyridin-2- 2.4 Hz, 1H),8.20-8.13 (m, 2H), 8.09 yl)-5-(1H-pyrazol-4- amine and pyrazole-4- (s,1H), 7.59-7.53 (m, 2H) 7.28 (br s, yl)pyridin-2-amine boronic acidpinacol ester; 2H); MS (ES+): m/z 341.3 (M + 1). 20% 1.10 3-(5-(2,5-5-bromo-3-(5-(4- ¹H NMR (400 MHz, DMSO-d₆): δ difluorophenyl)-fluorophenyl)-1,3,4- 8.51 (d, J = 2.4 Hz, 1H), 8.39 (d, J =1,3,4-oxadiazol-2- oxadiazol-2-yl)-pyridin-2- 2.4 Hz, 1H), 8.30-8.24 (m,2H), 8.21 yl)-5-(1H-pyrazol-4- amine and pyrazole-4- (s, 1H), 7.97 (s,1H), 7.49-7.42 (m, yl)pyridin-2-amine boronic acid pinacol ester; 2H),7.24 (br s, 2H); MS (ES+): m/z 26% 323.3 (M + 1). 1.11 3-(5-(2,6-5-bromo-3-(5-(2,6- ¹H NMR (400 MHz, CDCl₃): δ 8.40 dichlorophenyl)-dichlorophenyl)-1,3,4- (d, J = 2.0 Hz, 1H), 8.13 (d, J = 2.41,3,4-oxadiazol-2- oxadiazol-2-yl)-pyridin-2- Hz, 1H), 7.72 (s, 1H),7.64 (s, 1H), yl)-5-(1-cyclohexyl- amine and 1-cyclohexyl-4- 7.52-7.48(m, 3H), 6.86-6.60 (br s, 1H-pyrazol-4- (4,4,5,5-tetramethyl-1,3,2- 2H),4.15-4.11 (m, 1H), 2.24-2.16 yl)pyridin-2-amine dioxaborolan-2-yl)-1H-(m, 2H), 1.96-1.86 (m, 2H), 1.76- pyrazole; 38% 1.70 (m, 2H), 1.45-1.39(m, 2H), 1.33-1.20 (m, 2H). MS (ES+): m/z 455.3, 456.3 and 457.3 (M +1).

Example 2 SYNTHESIS OF3-(3-PHENYL-1,2,4-OXADIAZOL-5-YL)-5-(1-(TETRAHYDRO-2H-PYRAN-4-YL)-1H-PYRAZOL-4-YL)PYRIDIN-2-AMINE

A mixture of 5-bromo-3-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin-2-amine(100 mg, 0.33 mmol),1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.11 g, 0.40 mmol) and cesium carbonate (0.54 g, 1.65 mmol) in 5 mL of10:1 dioxane:water in a sealed tube was degassed for 10 min, followed bythe addition of tetrakis(triphenylphosphine)palladium(0) (38 mg, 0.03mmol). The mixture was degassed for another 10 minutes and then heatedat 100° C. overnight. After removal of the solvents in vacuo, theresidue was purified by column chromatography eluted with ethyl acetateto afford the title compound as a yellowish solid in 20% yield (25 mg).¹H NMR (400 MHz, DMSO-d₆): δ 8.48 (s, 1H), 8.35 (d, J=2.4 Hz, 1H),8.20-8.14 (m, 2H), 7.79 (s, 1H), 7.71 (s, 1H), 7.58-7.50 (m, 3H), 6.66(br s, 2H), 4.48-4.38 (m, 1H), 4.20-4.10 (m, 2H), 3.62-3.55 (m, 2H),2.22-2.10 (m, 4H); MS (ES+): m/z 389.3 (M+1).

The table below shows additional examples of compounds of Formula (IA5)that were prepared according to the above process.

Ex. No. Chemical Name Starting Material and Yield Characterization Data2.1 tert-butyl 4-(4-(6- tert-butyl 4-(4-(4,4,5,5- ¹H NMR (400 MHz,CDCl₃): δ 8.45 amino-5-(3-phenyl- tetramethyl-1,3,2- (d, J = 2.4 Hz,1H), 8.32 (d, J = 2.4 1,2,4-oxadiazol-5- dioxaborolan-2-yl)-1H- Hz, 1H),8.17-8.12 (m, 2H), 7.78 (s, yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1- 1H), 7.68 (s, 1H), 7.56-7.50 (m, 3H),pyrazol-1- carboxylate and 5-bromo-3- 6.68 (br s, 2H), 4.38-4.22 (m,3H), yl)piperidine-1- (3-phenyl-1,2,4-oxadiazol- 3.00-2.84 (m, 2H),2.24-2.14 (m, carboxylate 5-yl)pyridin-2-amine; 60% 2H), 2.06-1.92 (m,2H), 1.49 (s, 9H). 2.2 tert-butyl 4-(4-(6- tert-butyl 4-(4-(4,4,5,5- ¹HNMR (400 MHz, CDCl₃): δ 8.83 amino-5-(5-(pyridin- tetramethyl-1,3,2- (d,J = 4.8 Hz, 1H), 8.39 (d, J = 2.4 2-yl)-1,3,4-oxadiazol-dioxaborolan-2-yl)-1H- Hz, 1H), 8.34 (d, J = 8.0 Hz, 1H),2-yl)pyridin-3-yl)- pyrazol-1-yl)piperidine-1- 8.31 (d, J = 2.4 Hz, 1H),7.96-7.90 1H-pyrazol-1- carboxylate and 5-bromo-3- (m, 1H), 7.77 (s,1H), 7.70 (s, 1H), yl)piperidine-1- (5-(pyridin-2-yl)-1,3,4- 7.54-7.48(m, 1H), 6.85-6.65 (br s, carboxylate oxadiazol-2-yl)pyridin-2- 2H),4.38-4.20 (m, 3H), 3.00-2.85 amine; 46% (m, 2H), 2.22-2.14 (m, 2H),2.04- 1.90 (m, 2H), 1.49 (s, 9H). 2.3 tert-butyl 4-(4-(6- tert-butyl4-(4-(4,4,5,5- ¹H NMR (400 MHz, CDCl₃): δ 9.36 amino-5-(5-(pyridin-tetramethyl-1,3,2- (s, 1H), 8.81 (dd, J = 4.8, 1.2 Hz,3-yl)-1,3,4-oxadiazol- dioxaborolan-2-yl)-1H- 1H), 8.43 (dt, J = 8.0,2.0 Hz, 1H), 2-yl)pyridin-3-yl)- pyrazol-1-yl)piperidine-1- 8.39 (d, J =2.4 Hz, 1H), 8.13 (d, J = 1H-pyrazol-1- carboxylate and 5-bromo-3- 2.4Hz, 1H), 8.07 (s, 1H), 7.76 (s, yl)piperidine-1-(5-(pyridin-3-yl)-1,3,4- 1H), 7.67 (s, 1H), 6.75-6.60 (br s, carboxylateoxadiazol-2-yl)pyridin-2- 2H), 4.38-4.20 (m, 3H), 3.00-2.85 amine; 34%(m, 2H), 2.22-2.14 (m, 2H), 2.04- 1.90 (m, 2H), 1.47 (s, 9H). 2.4tert-butyl 4-(4-(6- tert-butyl 4-(4-(4,4,5,5- ¹H NMR (400 MHz, CDCl₃): δ9.57 amino-5-(5-(pyrazin- tetramethyl-1,3,2- (s, 1H), 8.80 (s, 2H), 8.42(s, 1H), 2-yl)-1,3,4-oxadiazol- dioxaborolan-2-yl)-1H- 8.28 (s, 1H),7.78 (s, 1H), 7.69 (s, 2-yl)pyridin-3-yl)- pyrazol-1-yl)piperidine-1-1H), 6.85-6.65 (br s, 2H), 4.38-4.20 1H-pyrazol-1- carboxylate and5-bromo-3- (m, 3H), 3.00-2.85 (m, 2H), 2.22- yl)piperidine-1-(5-(pyrazin-2-yl)-1,3,4- 2.14 (m, 2H), 2.04-1.90 (m, 2H), carboxylateoxadiazol-2-yl)pyridin-2- 1.49 (s, 9H). amine; 62% 2.5 tert-butyl4-(4-(6- tert-butyl 4-(4-(4,4,5,5- ¹H NMR (400 MHz, CDCl₃): δ 8.35amino-5-(5- tetramethyl-1,3,2- (d, J = 2.4 Hz, 1H), 8.05 (d, J = 2.4(cyclopropylmethyl)- dioxaborolan-2-yl)-1H- Hz, 1H), 7.74 (s, 1H), 7.64(s, 1H), 1,3,4-oxadiazol-2- pyrazol-1-yl)piperidine-1- 6.70-6.55 (br s,2H), 4.38-4.20 (m, yl)pyridin-3-yl)-1H- carboxylate and 5-bromo-3- 3H),3.00-2.86 (m, 2H), 2.86 (d, J = pyrazol-1- (5-(cyclopropylmethyl)- 6.4Hz, 2H), 2.22-2.14 (m, 2H), yl)piperidine-1- 1,3,4-oxadiazol-2-2.04-1.90 (m, 2H), 1.48 (s, 9H), carboxylate yl)pyridin-2-amine; 46%1.28-1.18 (m, 1H), 0.70-0.58 (m, 2H), 0.38-0.28 (m, 2H). 2.6 tert-butyl4-(4-(6- tert-butyl 4-(4-(4,4,5,5- ¹H NMR (400 MHz, CDCl₃): δ 8.34amino-5-(5-benzyl- tetramethyl-1,3,2- (d, J = 2.4 Hz, 1H), 7.99 (d, J =2.4 1,3,4-oxadiazol-2- dioxaborolan-2-yl)-1H- Hz, 1H), 7.72 (s, 1H),7.62 (s, 1H), yl)pyridin-3-yl)-1H- pyrazol-1-yl)piperidine-1- 7.41-7.29(m, 5H), 6.70-6.50 (br s, pyrazol-1- carboxylate and 3-(5- 2H),4.38-4.20 (m, 5H), 3.00-2.85 yl)piperidine-1- benzyl-1,3,4-oxadiazol-2-(m, 2H), 2.22-2.14 (m, 2H), 2.04- carboxylate yl)-5-bromopyridin-2- 1.90(m, 2H), 1.49 (s, 9H). amine; 36% 2.7 tert-butyl 4-(4-(6- tert-butyl4-(4-(4,4,5,5- ¹H NMR (400 MHz, CDCl₃): δ 8.41 amino-5-(5-(thiazol-tetramethyl-1,3,2- (d, J = 2.4 Hz, 1H), 8.28 (d, J = 2.42-yl)-1,3,4-oxadiazol- dioxaborolan-2-yl)-1H- Hz, 1H), 8.13 (d, J = 2.4Hz, 1H), 2-yl)pyridin-3-yl)- pyrazol-1-yl)piperidine-1- 7.77 (s, 1H),7.71-7.68 (m, 2H), 1H-pyrazol-1- carboxylate and 5-bromo-3- 6.85-6.65(br s, 2H), 4.38-4.20 (m, yl)piperidine-1- (5-(thiazol-2-yl)-1,3,4- 3H),3.00-2.86 (m, 2H), 2.22-2.14 carboxylate oxadiazol-2-yl)pyridin-2- (m,2H), 2.04-1.90 (m, 2H), 1.48 (s, amine; 62% 9H). 2.8 tert-butyl 4-(4-(6-tert-butyl 4-(4-(4,4,5,5- ¹H NMR (400 MHz, CDCl₃): δ 8.43 amino-5-(5-(4-tetramethyl-1,3,2- (d, J = 2.4 Hz, 1H), 8.28 (d, J = 2.4(trifluoromethyl)thiazol- dioxaborolan-2-yl)-1H- Hz, 1H), 8.07 (s, 1H),7.79 (s, 1H), 2-yl)-1,3,4- pyrazol-1-yl)piperidine-1- 7.73 (s, 1H),6.70-6.55 (br s, 2H), oxadiazol-2- carboxylate and 5-bromo-3- 4.38-4.20(m, 3H), 3.00-2.84 (m, yl)pyridin-3-yl)-1H- (5-(4- 2H), 2.24-2.16 (m,2H), 2.05-1.93 pyrazol-1- (trifluoromethyl)thiazol-2- (m, 2H), 1.48 (s,9H). yl)piperidine-1- yl)-1,3,4-oxadiazol-2- carboxylateyl)pyridin-2-amine; 36% 2.9 3-(5-phenyl-1,2,4- 4-(4,4,5,5-tetramethyl-¹H NMR (400 MHz, CD₃OD): δ 8.60 oxadiazol-3-yl)-5-1,3,2-dioxaborolan-2-yl)- (d, J = 2.4 Hz, 1H), 8.38 (d, J = 2.4(1H-pyrazol-4- 1H-pyrazole and 5-bromo- Hz, 1H), 8.27-8.22 (m, 2H), 7.96(br yl)pyridin-2-amine 3-(5-phenyl-1,2,4- s, 2H), 7.71-7.65 (m, 1H),7.64-7.59 oxadiazol-3-yl)pyridin-2- (m, 2H); MS (ES+): m/z 305.3 amine;5% (M + 1). 2.10 3-(3-phenyl-1,2,4- 4-(4,4,5,5-tetramethyl- ¹H NMR (400MHz, 15% CD₃OD in oxadiazol-5-yl)-5- 1,3,2-dioxaborolan-2-yl)- CDCl₃): δ8.42 (d, J = 2.0 Hz, 1H), (1H-pyrazol-4- 1H-pyrazole and 5-bromo- 8.35(d, J = 2.4 Hz, 1H), 8.15-8.09 yl)pyridin-2-amine 3-(3-phenyl-1,2,4- (m,2H), 7.81 (s, 2H), 7.54-7.46 (m, oxadiazol-5-yl)pyridin-2- 3H). MS(ES+): m/z 305.3 (M + H). amine; 5% 2.11 tert-butyl 4-(4-(6- tert-butyl4-(4-(4,4,5,5- ¹H NMR (400 MHz, CDCl₃): δ 8.35 amino-5-(5-tetramethyl-1,3,2- (d, J = 2.0 Hz, 1H), 8.03 (d, J = 2.0cyclohexyl-1,3,4- dioxaborolan-2-yl)-1H- Hz, 1H), 7.75 (s, 1H), 7.65 (s,1H), oxadiazol-2- pyrazol-1-yl)piperidine-1- 6.59 (br s, 2H), 4.38-4.34(m, 3H), yl)pyridin-3-yl)-1H- carboxylate and 5-bromo-3- 3.05-2.97 (m,1H), 2.97-2.85 (m, pyrazol-1- (5-cyclohexyl-1,3,4- 2H), 2.23-2.12 (m,4H), 2.05-1.98 yl)piperidine-1- oxadiazol-2-yl)pyridin-2- (m, 2H),1.95-1.86 (m, 2H), 1.81- carboxylate amine; 33% 1.63 (m, 4H), 1.49 (s,9H), 1.46-1.38 (m, 2H). 2.12 5-(1-cyclohexyl-1H-5-bromo-3-(3-phenyl-1,2,4- ¹H NMR (400 MHz, CDCl₃): δ 8.47pyrazol-4-yl)-3-(3- oxadiazol-5-yl)pyridin-2- (d, J = 2.4 Hz, 1H), 8.34(d, J = 2.4 phenyl-1,2,4- amine and 1-cyclohexyl-4- Hz, 1H), 8.19-1.14(m, 2H), 7.78 (s, oxadiazol-5- (4,4,5,5-tetramethyl-1,3,2- 1H), 7.69 (s,1H), 7.57-7.51 (m, 3H), yl)pyridin-2-amine dioxaborolan-2-yl)-1H- 6.65(br s, 2H), 4.23-4.13 (m, 1H), pyrazole; 15% 2.28-2.20 (m, 2H),1.98-1.91 (m, 2H), 1.85-1.74 (m, 3H), 1.54-1.40 (m, 2H), 1.37-1.29 (m,1H); MS (ES+) m/z 387.4 (M + 1). 2.13 3-(5-(2,6- 5-bromo-3-(5-(2,6- ¹HNMR (400 MHz, CDCl₃): δ 8.44 dichlorophenyl)- dichlorophenyl)-1,3,4- (d,J = 2.4 Hz, 1H), 8.12 (d, J = 2.4 1,3,4-oxadiazol-2-yl)-oxadiazol-2-yl)pyridin-2- Hz, 1H), 7.74 (s, 1H), 7.66 (s, 1H),5-(1-(tetrahydro-2H- amine and 1-(tetrahydro 7.52-7.49 (m, 3H),6.70-6.55 (br s, pyran-4-yl)-1H- 2H-pyran-4-yl)-4-(4,4,5,5- 2H),4.42-4.36 (m, 1H), 4.16-4.10 pyrazol-4-yl)pyridin- tetramethyl-1,3,2-(m, 2H), 3.60-3.50 (m, 2H), 2.16- 2-amine dioxaborolan-2-yl)-1H- 2.06(m, 4H). MS (ES+): m/z 457.2 pyrazole; 35% and 459.2 (M + 1). 2.145-(1-(tetrahydro-2H- 1-(tetrahydro-2H-pyran-4- ¹H NMR (400 MHz, CDCl₃):δ 8.41 pyran-4-yl)-1H- yl)-4-(4,4,5,5-tetramethyl- (d, J = 2.4 Hz, 1H),8.20-8.14 (m, pyrazol-4-yl)-3-(5- 1,3,2-dioxaborolan-2-yl)- 3H), 7.79(s, 1H), 7.70 (s, 1H), 7.63- phenyl-1,3,4- 1H-pyrazole and 5-bromo- 7.54(m, 3H), 6.75-6.50 (br s, 2H), oxadiazol-2- 3-(5-phenyl-1,3,4- 4.47-4.38(m, 1H), 4.19-4.14 (m, yl)pyridin-2-amine oxadiazol-2-yl)pyridin-2- 2H),3.63-3.54 (m, 2H), 2.23-2.10 amine; 50% (m, 4H). MS (ES+): m/z 389.4(M + 1), 411.4 (M + Na). 2.15 5-(1-cyclohexyl-1H-1-cyclohexyl-4-(4,4,5,5- ¹H NMR (400 MHz, CDCl₃): δ 8.40pyrazol-4-yl)-3-(5- tetramethyl-1,3,2- (d, J = 2.4 Hz, 1H), 8.20-8.14(m, phenyl-1,3,4- dioxaborolan-2-yl)-1H- 3H), 7.76 (s, 1H), 7.68 (s,1H), 7.63- oxadiazol-2- pyrazole and 5-bromo-3-(5- 7.54 (m, 3H),6.70-6.50 (br s, 2H), yl)pyridin-2-amine phenyl-1,3,4-oxadiazol-2-4.20-4.13 (m, 1H), 2.38-2.30 (m, yl)pyridin-2-amine; 8% 2H), 2.00-1.90(m, 2H), 1.85-1.75 (m, 3H), 1.54-1.40 (m, 2H), 1.37- 1.25 (m, 1H). MS(ES+): m/z 387.4 (M + 1), 409.4 (M + Na). 2.16 tert-butyl 4-(4-(6-5-bromo-3-(3-(2,6- ¹H NMR (400 MHz, CDCl₃): δ 8.46 amino-5-(3-(2,6-dichlorophenyl)-1,2,4- (m, 1H), 8.37 (m, 1H), 7.78 (s, 1H),dichlorophenyl)- oxadiazol-5-yl)pyridin-2- 7.69 (s, 1H), 7.50-7.40 (m,3H), 1,2,4-oxadiazol-5- and tert-butyl 4-(4-(4,4,5,5- 6.70-6.50 (br s,2H), 4.37-4.14 (m, yl)pyridin-3-yl)-1H- tetramethyl-1,3,2- 3H),3.00-2.82 (m, 2H), 2.22-2.10 pyrazol-1- dioxaborolan-2-yl)-1H- (m, 2H),2.07-1.88 (m, 2H), 1.48 (s, yl)piperidine-1- pyrazol-1-yl)piperidine-1-9H). carboxylate carboxylate; 20% 2.17 3-(3-(2,6- 5-bromo-3-(3-(2,6- ¹HNMR (400 MHz, CDCl₃): δ 8.48 dichlorophenyl)- dichlorophenyl)-1,2,4- (d,J = 2.0 Hz, 1H), 8.38 (d, J = 2.4 1,2,4-oxadiazol-5-yl)-oxadiazol-5-yl)pyridin-2- Hz, 1H), 7.79 (s, 1H), 7.71 (s, 1H),5-(1-(tetrahydro-2H- amine and 1-(tetrahydro 7.50-7.41 (m, 3H), 6.54 (brs, 2H), pyran-4-yl)-1H- 2H-pyran-4-yl)-4-(4,4,5,5- 4.48-4.37 (m, 1H),4.19-4.13 (m, pyrazol-4-yl)pyridin- tetramethyl-1,3,2- 2H), 3.62-3.55(m, 2H), 2.22-2.12 2-amine dioxaborolan-2-yl)-1H- (m, 4H); MS (ES+): m/z457.2, 458.2 pyrazole; 6% and 459.2 (M + 1). 2.18 3-(3-(2,6-5-bromo-3-(3-(2,6- ¹H NMR (400 MHz, CDCl₃): δ 8.48 dichlorophenyl)-dichlorophenyl)-1,2,4- (d, J = 2.4 Hz, 1H), 8.38 (d, J = 2.41,2,4-oxadiazol-5-yl)- oxadiazol-5-yl)pyridin-2- Hz, 1H), 7.77 (s, 1H),7.69 (s, 1H), 5-(1-cyclohexyl-1H- amine and 1-cyclohexyl-4- 7.49-7.41(m, 3H), 6.54 (br s, 2H), pyrazol-4-yl)pyridin-(4,4,5,5-tetramethyl-1,3,2- 4.22-4.13 (m, 1H), 2.28-2.22 (m, 2-aminedioxaborolan-2-yl)-1H- 2H), 1.96-1.93 (m, 2H), 1.81-1.75 pyrazole; 20%(m, 3H), 1.53-1.49 (m, 2H), 1.48- 1.46 (m, 1H); MS (ES+): m/z 455.3,456.3 and 457.3 (M + 1). 2.19 tert-butyl 4-(3-(6- 5-bromo-3-(5-(2,6- ¹HNMR (400 MHz, CDCl₃): δ 8.45 amino-5-(5-(2,6- dichlorophenyl)-1,3,4- (d,J = 2.4 Hz, 1H), 8.13 (J = 2.4 Hz, dichlorophenyl)-oxadiazol-2-yl)pyridin-2- 1H), 7.53-7.48 (m, 3H), 6.99-6.971,3,4-oxadiazol-2- amine and tert-butyl 4-(3- (m, 1H), 6.78-6.75 (m,1H), 6.55 (br yl)pyridin-3-yl)-1H- (4,4,5,5-tetramethyl-1,3,2- s, 2H),6.43-6.40 (m, 1H), 4.35-4.22 pyrrol-1- dioxaborolan-2-yl)-1H- (m, 2H),4.02-3.92 (m, 1H), 2.80- yl)piperidine-1- pyrrol-1-yl)piperidine-1- 2.78(m, 2H), 2.12-2.05 (m, 2H), carboxylate carboxylate; 46% 1.92-1.80 (m,2H), 1.48 (s, 9H).

Example 3 SYNTHESIS OF3-(5-(2,6-DICHLORO-3-FLUOROPHENYL)-1,3,4-OXADIAZOL-2-YL)-5-(1-PIPERIDIN-4-YL)-1H-PYRAZOL-4-YL)PYRIDIN-2-AMINE

To a solution of tert-butyl4-(4-(6-amino-5-(5-(2,6-dichloro-3-fluorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(30.0 mg, 0.052 mmol) in dichloromethane (3 mL) was added a solution of2 N hydrochloric acid in diethyl ether (1.00 mL, 2.00 mmol). The mixturewas stirred at ambient temperature overnight, diluted with saturatedsodium bicarbonate (5 mL), and extracted with dichloromethane (3×20 mL).The combined extracts were washed with brine (10 mL), dried andevaporated to afford the title compound as a pale brown solid in 92%yield (23 mg). ¹H NMR (400 Hz, CDCl₃): δ 8.43 (d, J=2.4 Hz, 1H), 8.11(d, J=2.4 Hz, 1H), 7.74 (d, J=0.8 Hz, 1H), 7.66 (d, J=0.8 Hz, 1H),7.53-7.48 (m, 1H), 7.41-7.36 (m, 1H), 6.61 (br s, 2H), 4.30-4.21 (m,1H), 3.30-3.23 (m, 2H), 2.83-2.75 (m, 2H), 2.23-2.17 (m, 2H), 1.98-1.87(m, 2H); MS (ES+): m/z 474.2, 475.2 and 476.3 (M+1).

The table below shows additional examples of compounds of Formula (IA4)that were prepared according to the above process.

Ex. No. Chemical Name Starting Material and Yield Characterization Data3.1 3-(5-phenyl-1,3,4- tert-butyl 4-(4-(6-amino-5- ¹H NMR (400 MHz,CDCl₃): δ 8.40 oxadiazol-2-yl)-5- (5-phenyl)-1,3,4-oxadiazol- (d, J =2.4 Hz, 1H), 8.19-8.15 (m, (1-(piperidin-4-yl)- 2-yl)pyridin-3-yl)-1H-3H), 7.77 (d, J = 0.8 Hz, 1H), 7.70 (d, 1H-pyrazol-4-pyrazol-1-yl)piperidine-1- J = 0.8 Hz, 1H), 7.61-7.55 (m, 3H),yl)pyridin-2-amine carboxylate; 76% 6.59 (br s, 2H), 4.34-4.25 (m, 1H),3.32-3.25 (m, 2H), 2.85-2.77 (m, 2H), 2.26-2.19 (m, 2H), 2.03-1.91 (m,2H); MS (ES+): m/z 388.3 (M + 1). 3.2 3-(5-(4-(tert- tert-butyl4-(4-(5-(5-(4-tert- ¹H NMR (300 Hz, CDCl₃): δ 8.39 (d,butyl)phenyl)-1,3,4- butylphenyl)-1,3,4- J = 2.4 Hz, 1H), 8.16 (d, J =2.4 Hz, oxadiazol-2-yl)-5- oxadiazol-2-yl)-6- 1H), 8.11-8.06 (m, 2H),7.77 (s, 1H), (1-(piperidin-4-yl)- aminopyridin-3-yl)-1H- 7.70 (s, 1H),7.61-7.56 (m, 2H), 6.60 1H-pyrazol-4- pyrazol-1-yl)piperidine-1- (br s,2H), 4.35-4.27 (m, 1H), 3.36- yl)pyridin-2-amine carboxylate; 100% 3.28(m, 2H), 2.88-2.78 (m, 2H), 2.28- 2.23 (m, 2H), 2.07-1.95 (m, 2H), 1.38(s, 9H); MS (ES+): m/z 444.4 (M + 1). 3.3 3-(5-(2,5- tert-butyl4-(4-(6-amino-5- ¹H NMR (300 Hz, CDCl₃) δ 8.42 (d, J = difluorophenyl)-(5-(2,5-difluorophenyl)- 2.4 Hz, 1H), 8.16 (d, J = 2.4 Hz,1,3,4-oxadiazol-2- 1,3,4-oxadiazol-2- 1H), 7.90-7.84 (m, 1H), 7.76 (s,1H), yl)-5-(1-piperidin-4- yl)pyridin-3-yl)-1H- 7.68 (s, 1H), 7.30-7.26(m, 2H), 6.58 yl)-1H-pyrazol-4- pyrazol-1-yl)piperidine-1- (br s, 2H),4.33-4.24 (m, 1H), 3.31- yl)pyridin-2-amine carboxylate; 88% 3.24 (m,2H), 2.85-2.75 (m, 2H), 2.26- 2.17 (m, 2H), 2.02-1.90 (m, 2H); MS (ES+):m/z 424.3 (M + 1). 3.4 3-(5-(2,6- tert-butyl 4-(4-(6-amino-5- ¹H NMR(300 Hz, CDCl₃) δ 8.42 (d, J = dichlorophenyl)- (5-(2,6-dichlorophenyl)-2.4 Hz, 1H), 8.12 (d, J = 2.4 Hz, 1,3,4-oxadiazol-2- 1,3,4-oxadiazol-2-1H), 7.73 (s, 1H), 7.66 (s, 1H), 7.54- yl)-5-(1-piperidin-4-yl)pyridin-3-yl)-1H- 7.47 (m, 3H), 6.62 (br s, 2H), 4.31-yl)-1H-pyrazol-4- pyrazol-1-yl)piperidine-1- 4.20 (m, 1H), 3.31-3.22 (m,2H), 2.84- yl)pyridin-2-amine carboxylate; 90% 2.73 (m, 2H), 2.24-2.16(m, 2H), 1.98- 1.76 (m, 2H); MS (ES+): m/z 456.2, 457.3 and 458.3 (M +1). 3.5 3-(5-(4- tert-butyl 4-(4-(6-amino-5- ¹H NMR (300 Hz, CDCl₃): δ8.40 (d, fluorophenyl)-1,3,4- (5-(4-fluorophenyl)-1,3,4- J = 2.4 Hz,1H), 8.21-8.15 (m, 2H), oxadiazol-2-yl)-5- oxadiazol-2-yl)pyridin-3-8.14 (d, J = 2.4 Hz, 1H), 7.77 (d, J = (1-piperidin-4-yl)-yl)-1H-pyrazol-1- 0.8 Hz, 1H), 7.70 (d, J = 0.8 Hz, 1H), 1H-pyrazol-4-yl)piperidine-1-carboxylate; 7.30-7.24 (m, 2H), 6.60 (br s, 2H),yl)pyridin-2-amine 87% 4.33-4.25 (m, 1H), 3.32-3.25 (m, 2H), 2.85-2.76(m, 2H), 2.26-2.18 (m, 2H), 2.02-1.90 (m, 2H); MS (ES+): m/z 406.4 (M +1). 3.6 3-(3-phenyl-1,2,4- tert-butyl 4-(4-(6-amino-5- ¹H NMR (400 MHz,CDCl₃): δ 8.46 oxadiazol-5-yl)-5- (3-phenyl-1,2,4-oxadiazol- (d, J = 2.4Hz, 1H), 8.34 (d, J = 2.4 (1-(piperidin-4-yl)- 5-yl)pyridin-3-yl)-1H-Hz, 1H), 8.18-8.12 (m, 2H), 7.77 (s, 1H-pyrazol-4-pyrazol-1-yl)-piperidine-1- 1H), 7.70 (s, 1H), 7.58-7.50 (m, 3H),yl)pyridin-2-amine carboxylate; 77% 6.66 (br s, 2H), 4.32-4.22 (m, 1H),3.32-3.22 (m, 2H), 2.85-2.74 (m, 2H), 2.26-2.17 (m, 2H), 2.00-1.88 (m,2H); MS (ES+): m/z 388.4 (M + 1). 3.7 3-(5- tert-butyl 4-(4-(6-amino-5-¹H NMR (400 MHz, CD₃OD): δ 8.36 (cyclopropylmethyl)-(5-(cyclopropylmethyl)- (d, J = 2.4 Hz, 1H), 8.20 (d, J = 2.41,3,4-oxadiazol-2- 1,3,4-oxadiazol-2- Hz, 1H), 8.06 (s, 1H), 7.82 (s,1H), yl)-5-(1-(piperidin- yl)pyridin-3-yl)-1H- 4.45-4.35 (m, 1H),3.38-3.30 (m, 2H), 4-yl)-1H-pyrazol-4- pyrazol-1-yl)piperidine-1-2.98-2.88 (m, 2H), 2.87 (d, J = 8.0 yl)pyridin-2-amine carboxylate; 77%Hz, 2H), 2.24-2.16 (m, 2H), 2.14-2.02 (m, 2H), 1.28-1.17 (m, 1H),0.67-0.61 (m, 2H), 0.38-0.32 (m, 2H); MS (ES+): m/z 366.4 (M + 1). 3.85-(1-(piperidin-4- tert-butyl 4-(4-(6-amino-5- ¹H NMR (400 MHz, CD₃OD):δ 8.79 yl)-1H-pyrazol-4- (5-(pyridin-2-yl)-1,3,4- (d, J = 4.4 Hz, 1H),8.73 (d, J = 2.4 yl)-3-(5-(pyridin-2- oxadiazol-2-yl)pyridin-3- Hz, 1H),8.42 (d, J = 2.4 Hz, 1H), yl)-1,3,4-oxadiazol- yl)-1H-pyrazol-1- 8.38(d, J = 12.0 Hz, 1H), 8.19 (s, 2-yl)pyridin-2-yl)piperidine-1-carboxylate; 1H), 8.13-8.06 (m, 1H), 7.97 (s, 1H), amine61% 7.69-7.64 (m, 1H), 4.65-4.56 (m, 1H), 3.63-3.55 (m, 2H), 3.30-3.20(m, 2H), 2.42-2.26 (m, 4H); MS (ES+): m/z 389.3 (M + 1). 3.95-(1-(piperidin-4- tert-butyl 4-(4-(6-amino-5- ¹H NMR (400 MHz, CD₃OD):δ 9.36 yl)-1H-pyrazol-4- (5-(pyridin-3-yl)-1,3,4- (d, J = 1.6 Hz, 1H),8.81-8.76 (m, yl)-3-(5-(pyridin-3- oxadiazol-2-yl)pyridin-3- 1H),8.65-8.60 (m, 1H), 8.46 (d, J = yl)-1,3,4-oxadiazol- yl)-1H-pyrazol-1-2.4 Hz, 1H), 8.40 (d, J = 2.4 Hz, 1H), 2-yl)pyridin-2-yl)piperidine-1-carboxylate; 8.17 (d, J = 0.4 Hz, 1H), 7.96 (d, J =amine 68% 0.8 Hz, 1H), 7.70-7.75 (m, 1H), 4.62- 4.53 (m, 1H), 3.50-3.42(m, 2H), 3.26- 3.17 (m, 2H), 2.40-2.24 (m, 4H); MS (ES+): m/z 389.4 (M +1). 3.10 5-(1-(piperidin-4- tert-butyl 4-(4-(6-amino-5- ¹H NMR (400 MHz,CD₃OD): δ 9.54 yl)-1H-pyrazol-4- (5-(pyrazin-2-yl)-1,3,4- (d, J = 1.6Hz, 1H), 8.87-8.82 (m, yl)-3-(5-(pyrazin-2- oxadiazol-2-yl)pyridin-3-2H), 8.80 (d, J = 2.4 Hz, 1H), 8.45 (d, yl)-1,3,4-oxadiazol-yl)-1H-pyrazol-1- J = 2.4 Hz, 1H), 8.28 (d, J = 0.40 Hz, 2-yl)pyridin-2-yl)piperidine-1-carboxylate; 1H), 7.99 (d, J = 0.80 Hz, 1H), 4.66- amine100% 4.57 (m, 1H), 3.62-3.54 (m, 2H), 3.30- 3.20 (m, 2H), 2.42-2.26 (m,4H); MS (ES+): m/z 390.4 (M + 1). 3.11 3-(5-benzyl-1,3,4- tert-butyl4-(4-(6-amino-5- ¹H NMR (400 MHz, CD₃OD): δ 8.34 oxadiazol-2-yl)-5-(5-benzyl-1,3,4-oxadiazol- (d, J = 2.4 Hz, 1H), 8.14 (d, J = 2.4(1-(piperidin-4-yl)- 2-yl)pyridin-3-yl)-1H- Hz, 1H), 8.05 (d, J = 0.80Hz, 1H), 1H-pyrazol-4- pyrazol-1-yl)piperidine-1- 7.82 (d, J = 0.80 Hz,1H), 7.39-7.25 yl)pyridin-2-amine carboxylate; 57% (m, 5H), 4.56-4.46(m, 1H), 4.33 (s, 2H), 3.54-3.46 (m, 2H), 3.19-3.10 (m, 2H), 2.34-2.16(m, 4H); MS (ES+): m/z 402.4 (M + 1). 3.12 5-(1-(piperidin-4- tert-butyl4-(4-(6-amino-5- ¹H NMR (400 MHz, CD₃OD): δ 8.80 yl)-1H-pyrazol-4-(5-(thiazol-2-yl)-1,3,4- (d, J = 2.0 Hz, 1H), 8.45 (d, J = 2.0yl)-3-(5-(thiazol-2- oxadiazol-2-yl)pyridin-3- Hz, 1H), 8.28 (s, 1H),8.18 (d, J = 2.8 yl)-1,3,4-oxadiazol- yl)-1H-pyrazol-1- Hz, 1H), 8.05(d, J = 3.2 Hz, 1H), 2-yl)pyridin-2- yl)piperidine-1-carboxylate; 7.99(s, 1H), 4.65-4.57 (m, 1H), 3.62- amine 80% 3.54 (m, 2H), 3.30-3.20 (m,2H), 2.42- 2.25 (m, 4H); MS (ES+): m/z 395.3 (M + 1). 3.135-(1-(piperidin-4- tert-butyl 4-(4-(6-amino-5- ¹H NMR (400 MHz, CD₃OD):δ 8.71 yl)-1H-pyrazol-4- (5-(4- (d, J = 2.0 Hz, 1H), 8.61 (s, 1H), 8.47yl)-3-(5-(4- (trifluoromethyl)thiazol-2- (d, J = 2.0 Hz, 1H), 8.26 (s,1H), 7.98 (trifluoromethyl)thiazol- yl)-1,3,4-oxadiazol-2-yl)- (s, 1H),4.65-4.55 (m, 1H), 3.51-3.42 2-yl)-1,3,4- pyridin-3-yl)-1H-pyrazol-1-(m, 2H), 3.28-3.18 (m, 2H), 2.40-2.24 oxadiazol-2-yl)piperidine-1-carboxylate; (m, 4H). MS (ES+): m/z 463.3 (M +yl)pyridin-2-amine 96% 1). 3.14 3-(5-cyclohexyl- tert-butyl4-(4-(6-amino-5- ¹H NMR (400 MHz, DMSO-d₆): δ 1,3,4-oxadiazol-2-(5-cyclohexyl-1,3,4- 8.45 (d, J = 2.4 Hz, 1H), 8.22 (s, 1H),yl)-5-(1-(piperidin- oxadiazol-2-yl)pyridin-3- 8.12 (d, J = 2.4 Hz, 1H),7.87 (s, 1H), 4-yl)-1H-pyrazol-4- yl)-1H-pyrazol-1- 7.19 (br s, 2H),4.28-4.19 (m, 1H), yl)pyridin-2-amine yl)piperidine-1-carboxylate;3.15-3.08 (m, 2H), 3.05-2.95 (m, 1H), 95% 2.75-2.65 (m, 2H), 2.13-1.97(m, 4H), 1.95-1.80 (m, 2H), 1.80-1.70 (m, 2H), 1.68-1.53 (m, 3H),1.45-1.32 (m, 2H), 1.32-1.24 (m, 1H); (ES+): m/z 394.4 (M + 1). 3.153-(3-(2,6- tert-butyl 4-(4-(6-amino-5- ¹H NMR (400 M Hz, CD₃OD): δ 8.49dichlorophenyl)- (3-(2,6-dichlorophenyl)- (d, J = 2.4 Hz, 1H), 8.47 (d,J = 2.4 1,2,4-oxadiazol-5- 1,2,4-oxadiazol-5- Hz, 1H), 8.11 (s, 1H),7.86 (s, 1H), yl)-5-(1-(piperidin- yl)pyridin-3-yl)-1H- 7.60-7.52 (m,3H), 4.37-4.27 (m, 1H), 4-yl)-1H-pyrazol-4- pyrazol-1-yl)piperidine-1-3.24-3.16 (m, 2H), 2.82-2.73 (m, 2H), yl)pyridin-2-amine carboxylate;98% 2.17-2.09 (m, 2H), 2.03-1.91 (m, 2H). MS (ES+): m/z 457.3, 458.3 and459.3 (M + 1). 3.16 3-(5-(2,6- tert-butyl 4-(3-(6-amino-5- ¹H NMR (400MHz, CDCl₃): δ 8.45 dichlorophenyl)- (5-(2,6-dichlorophenyl)- (d, J =2.4 Hz, 1H), 8.13 (d, J = 2.4 1,3,4-oxadiazol-2- 1,3,4-oxadiazol-2- Hz,1H), 7.53-7.46 (m, 3H), 7.01-6.98 yl)-5-(1-(piperidin-yl)pyridin-3-yl)-1H-pyrrol- (m, 1H), 6.79-6.76 (m, 1H), 6.52 (br s,4-yl)-1H-pyrrol-3- 1-yl)piperidine-1- 2H), 6.41-6.38 (m, 1H), 3.95-3.87(m, yl)pyridin-2-amine carboxylate; 69% 1H), 3.26-3.20 (m, 2H),2.78-2.70 (m, 2H), 2.13-2.06 (m, 2H), 1.92-1.82 (m, 2H); MS (ES+): m/z455.1, 456.1 and 457.1 (M + 1).

Example 4 SYNTHESIS OF1-(4-(4-(6-AMINO-5-(5-(2,6-DICHLOROPHENYL)-1,3,4-OXADIAZOL-2-YL)PYRIDIN-3-YL)-1H-PYRAZOL-1-YL)PIPERIDIN-1-YL)ETHANONE

To a solution of3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine(62.0 mg, 0.136 mmol) in dichloromethane (3 mL) was added aceticanhydride (0.013 mL, 0.136 mmol), followed by the addition oftriethylamine (0.098 mL, 0.700 mmol) at 0° C. The mixture was stirred atambient temperature for 3 h, diluted with dichloromethane (20 mL),washed with saturated sodium bicarbonate (10 mL) and brine (10 mL). Thevolatiles were removed in vacuo and the residue was purified by flashchromatography eluted with 5% methanol in dichloromethane to afford thetitle compound as a pale brown solid in 81% yield (55 mg). ¹H NMR (400Hz, CDCl₃): δ 8.35 (d, J=2.4 Hz, 1H), 8.19 (d, J=2.4 Hz, 1H), 7.41 (s,1H), 7.65 (s, 1H), 7.53-7.50 (m, 3H), 7.10 (br s, 2H), 4.79-4.72 (m,1H), 4.43-4.33 (m, 1H), 4.02-3.94 (m, 1H), 3.30-3.21 (m, 1H), 2.82-2.73(m, 1H), 2.30-2.16 (m, 2H), 2.14 (s, 3H), 2.04-1.90 (m, 2H); MS (ES+):m/z 498.3, 499.3 and 500.3 (M+1).

Example 4.1 SYNTHESIS OF1-(4-(4-(6-AMINO-5-(3-PHENYL-1,2,4-OXADIAZOL-5-YL)PYRIDIN-3-YL)-1H-PYRAZOL-1-YL)PIPERIDIN-1-YL)ETHANONE

Following the procedure as described in Example 4, making variationsusing3-(3-phenyl-1,2,4-oxadiazol-5-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amineto replace3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amineto react with acetic anhydride, the title compound was obtained as apale yellow solid in 60% yield. ¹H NMR (400 MHz, CDCl₃): δ 8.46 (d,J=2.4 Hz, 1H), 8.33 (d, J=2.4 Hz, 1H), 8.18-8.13 (m, 2H), 7.78 (s, 1H),7.68 (s, 1H), 7.57-7.50 (m, 3H), 6.67 (br s, 2H), 4.82-4.74 (m, 1H),4.44-4.35 (m, 1H), 4.04-3.96 (m, 1H), 3.32-3.22 (m, 1H), 2.85-2.76 (m,1H), 2.32-2.19 (m, 2H), 2.16 (s, 3H), 1.90-1.74 (m, 2H); MS (ES+): m/z430.5 (M+1).

Example 5 SYNTHESIS OF3-(5-(2,6-DICHLOROPHENYL)-1,3,4-OXADIAZOL-2-YL)-5-(1-(1-METHYLPIPERIDIN-4-YL)-1H-PYRAZOL-4-YL)PYRIDINE-2-AMINE

To a cooled (0° C.) solution of3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine(62.0 mg, 0.136 mmol) in dichloromethane/methanol (2 mL/2 mL) was added37% formaldehyde in water (0.0110 mL, 0.148 mmol). Sodiumcyanoborohydride (11.0 mg, 0.148 mmol) was added 10 minutes later. Themixture was stirred at 0° C. for 1 h, then at ambient temperature for 1h, and evaporated. The residue was purified by flash chromatographyeluted with 3-5% methanol in dichloromethane containing 0.1% ammoniumhydroxide to afford the title compound as a yellow solid in 81% yield(52 mg). ¹H NMR (400 Hz, CDCl₃): δ 8.41 (d, J=2.4 Hz, 1H), 8.11 (d,J=2.4 Hz, 1H), 7.22 (s, 1H), 7.66 (s, 1H), 7.53-7.48 (m, 3H), 6.62 (brs, 2H), 4.25-4.15 (m, 1H), 3.22-3.03 (m, 2H), 2.40 (s, 3H), 2.34-2.20(m, 4H), 2.20-2.08 (m, 2H); MS (ES+): m/z 470.3, 471.3 and 472.4 (M+1).

The table below shows additional examples of compounds of Formula (IA4)that were prepared according to the above process.

Ex. No. Chemical Name Starting Material and Yield Characterization Data5.1 5-(1-(1- 3-(5-phenyl-1,2,4- ¹H NMR (400 MHz, CDCl₃) δ 8.51methylpiperidin-4- oxadiazol-3-yl)-5-(1- (d, J = 2.4 Hz, 1H), 8.39 (d, J= 2.4 yl)-1H-pyrazol-4- (piperidin-4-yl)-1H-pyrazol- Hz, 1H), 8.27-8.23(m, 2H), 7.79 (s, yl)-3-(5-phenyl- 4-yl)pyridin-2-amine and 1H), 7.71(s, 1H), 7.67-7.62 (m, 1H), 1,2,4-oxadiazol-3- formaldehyde; 58%7.61-7.56 (m, 2H), 6.19 (br s, 2H), yl)pyridin-2-amine 4.23-4.14 (m,1H), 3.06-2.98 (m, 2H), 2.36 (s, 3H), 2.26-2.09 (m, 6H); (ES+): m/z402.4 (M + 1). 5.2 5-(1-(1- 3-(3-phenyl-1,2,4- ¹H NMR (400 MHz,DMSO-d₆): methylpiperidin-4- oxadiazol-5-yl)-5-(1- δ 8.60 (d, J = 2.4Hz, 1H), 8.39 (d, J = yl)-1H-pyrazol-4- (piperidin-4-yl)-1H-pyrazol- 2.4Hz, 1H), 8.33 (s, 1H), 8.17-8.13 yl)-3-(3-phenyl- 4-yl)pyridin-2-amineand (m, 2H), 7.96 (s, 1H), 7.63-7.54 (m, 1,2,4-oxadiazol-5-formaldehyde; 39% 3H), 7.48 (br s, 2H), 4.33-4.22 (m, yl)pyridin-2-amine1H), 3.24-3.12 (m, 2H), 2.73-2.60 (m, 2H), 2.52 (s, 3H), 2.20-2.00 (m,4H); MS (ES+): m/z 402.4 (M + 1). 5.3 3-(3-(2,6-3-(3-(2,6-dichlorophenyl)- ¹H NMR (400 MHz, CDCl₃): δ 8.47dichlorophenyl)- 1,2,4-oxadiazol-5-yl)-5-(1- (d, J = 2.4 Hz, 1H), 8.37(d, J = 2.4 1,2,4-oxadiazol-5- (piperidin-4-yl)-1H-pyrazol- Hz, 1H),7.76 (s, 1H), 7.69 (s, 1H), yl)-5-(1-(1- 4-yl)pyridin-2-amine and7.50-7.40 (m, 3H), 6.52 (br s, 2H), methylpiperidin-4- formaldehyde; 28%4.25-4.15 (m, 1H), 3.08-2.98 (m, 2H), yl)-1H-pyrazol-4- 2.37 (s, 3H),2.28-2.10 (m, 6H); MS yl)pyridin-2-amine (ES+): m/z 470.3, 471.3 and472.3 (M + 1). 5.4 3-(3-phenyl-1,2,4- 3-(3-phenyl-1,2,4- ¹H NMR (400MHz, CDCl₃): δ 8.46 oxadiazol-5-yl)-5- oxadiazol-5-yl)-5-(1- (d, J = 2.4Hz, 1H), 8.33 (d, J = 2.4 (1-(1-ethylpiperidin-(piperidin-4-yl)-1H-pyrazol- Hz, 1H), 8.19-8.14 (m, 2H), 7.77 (s,4-yl)-1H-pyrazol-4- 4-yl)pyridin-2-amine and 1H), 7.68 (s, 1H),7.57-7.50 (m, 3H), yl)pyridin-2-amine acetaldehyde; 43% 6.52 (br s, 2H),4.25-4.16 (m, 1H), 3.15-3.08 (m, 2H), 2.50 (q, J = 7.2 Hz, 2H),2.30-2.03 (m, 2H), 2.18-2.08 (m, 4H), 1.14 (t, J = 7.2 Hz, 3H); (ES+):m/z 416.4 (M + 1). 5.5 3-(3-(2,6- 3-(3-(2,6-dichlorophenyl)- ¹H NMR (400MHz, CDCl₃) δ 8.47 dichlorophenyl)- 1,2,4-oxadiazol-5-yl)-5-(1- (d, J =2.4 Hz, 1H), 8.37 (d, J = 2.0 1,2,4-oxadiazol-5-(piperidin-4-yl)-1H-pyrazol- Hz, 1H), 7.77 (s, 1H), 7.70 (s, 1H),yl)-5-(1-(1- 4-yl)pyridin-2-amine and 7.51-7.41 (m, 3H), 6.52 (br s,2H), dodecylpiperidin-4- dodecyl aldehyde; 20% 4.23-4.16 (m, 1H),3.13-3.06 (m, 2H), yl)-1H-pyrazol-4- 2.43-2.35 (m, 2H), 2.25-2.18 (m,2H), yl)pyridin-2-amine 2.16-2.06 (m, 4H), 1.55-1.47 (m, 2H), 1.35-1.24(m, 18H), 0.89 (t, J = 6.8 Hz, 3H); MS (ES+): m/z 624.5, 625.5 and 626.5(M + 1). 5.6 3-(3-(2,6- 3-(3-(2,6-dichlorophenyl)- ¹H NMR (400 MHz,CDCl₃): δ 8.46 dichlorophenyl)- 1,2,4-oxadiazol-5-yl)-5-(1- (s, 1H),8.36 (s, 1H), 7.76 (s, 1H), 1,2,4-oxadiazol-5-(piperidin-4-yl)-1H-pyrazol- 7.69 (s, 1H), 7.50-7.38 (m, 3H), 6.70-yl)-5-(1-(1- 4-yl)pyridin-2-amine and 6.40 (br s, 2H), 4.27-4.15 (m,1H), ethylpiperidin-4-yl)- acetaldehyde; 25% 3.60-3.50 (m, 2H),2.60-2.45 (m, 2H), 1H-pyrazol-4- 2.30-2.00 (m, 6H), 1.14 (t, J = 6.8 Hz,yl)pyridin-2-amine 3H); MS (ES+): m/z 484.3, 485.3 and 486.4 (M + 1).5.7 3-(5-(2,6- acetaldehyde and 3-(5-(2,6- ¹H NMR (400 MHz, CDCl₃): δ8.41 dichlorophenyl)- dichlorophenyl)-1,3,4- (d, J = 2.4 Hz, 1H), 8.11(d, J = 2.4 1,3,4-oxadiazol-2- oxadiazol-2-yl)-5-(1- Hz, 1H), 7.72 (s,1H), 7.66 (s, 1H), yl)-5-(1-(1- piperidin-4-yl)-1H-pyrazol- 7.53-7.46(m, 3H), 6.72-6.54 (br s, ethylpiperidin-4-yl)- 4-yl)pyridin-2-amine;61% 2H), 4.24-4.14 (m, 1H), 3.07-2.98 (m, 1H-pyrazol-4- 2H), 2.55-2.45(m, 2H), 2.28-2.04 (m, yl)pyridin-2-amine 6H), 1.33 (t, J = 7.2 Hz, 3H);MS (ES+): m/z 484.3, 485.3 and 486.3 (M + 1). 5.8 3-(5-(2,6- dodecylaldehyde and 3-(5- ¹H NMR (400 MHz, CDCl₃): δ 8.41 dichlorophenyl)-(2,6-dichlorophenyl)-1,3,4- (d, J = 2.4 Hz, 1H), 8.11 (d, J = 2.41,3,4-oxadiazol-2- oxadiazol-2-yl)-5-(1- Hz, 1H), 7.72 (s, 1H), 7.66 (s,1H), yl)-5-(1-(1- piperidin-4-yl)-1H-pyrazol- 7.54-7.46 (m, 3H),6.76-6.50 (br s, dodecylpiperidin-4- 4-yl)pyridin-2-amine; 51% 2H),4.23-4.13 (m, 1H), 3.13-3.05 (m, yl)-1H-pyrazol-4- 2H), 2.39 (t, J = 7.2Hz, 2H), 2.25- yl)pyridin-2-amine 2.00 (m, 6H), 1.55-1.45 (m, 2H),1.35-1.20 (m, 18H), 0.88 (t, J = 7.2 Hz, 3H). MS (ES+): m/z 624.4, 625.4and 626.4 (M + 1).

Example 6 SYNTHESIS OF1-(4-(4-(6-AMINO-5-(5-(2,6-DICHLOROPHENYL)-1,3,4-OXADIAZOL-2-YL)PYRIDIN-3-YL)-1H-PYRAZOL-1-YL)PIPERIDIN-1-YL)-4-METHYLPENTAN-1-ONE

To a mixture of3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine(63.0 mg, 0.138 mmol), 4-methylpentanoic acid (0.021 mL, 0.166 mmol) and1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (78.7 mg, 99%, 0.20 mmol) dissolved inN,N-dimethylformamide (1.0 mL) was added triethylamine (0.039 mL, 0.276mmol). The resulting mixture was stirred at ambient temperatureovernight, and diluted with ethyl acetate (30 mL), washed with brine(2×30 mL), and dried over sodium sulfate. After filtration and removalof the solvent, the residue was purified by column chromatography elutedwith dichloromethane:methanol:NH₄OH (from 200:6:1 to 200:8:1) to affordthe title compound as a yellow solid in 39% yield (30.0 mg). ¹H NMR (400MHz, CDCl₃): δ 8.38 (d, J=2.4 Hz, 1H), 8.12 (d, J=2.4 Hz, 1H), 7.73 (s,1H), 7.64 (s, 1H), 7.51-7.49 (m, 3H), 6.86-6.60 (br s, 2H), 4.80-4073(m, 1H), 4.40-4.35 (m, 1H), 4.04-3.98 (m, 1H), 3.25-3.18 (m, 1H),2.80-2.71 (m, 1H), 2.38-2.32 (m, 2H), 2.30-2.14 (m, 2H), 2.03-1.88 (m,2H), 1.67-1.49 (m, 3H), 0.91 (d, J=6.4 Hz, 6H). MS: (ES+): m/z 554.4,555.3, and 556.3 (M+1), 576.3, 577.3 and 578.3 (M+Na).

Example 7 SYNTHESIS OF(4-(4-(6-AMINO-5-(3-PHENYL-1,2,4-OXADIAZOL-5-YL)PYRIDIN-3-YL)-1H-PYRAZOL-1-YL)PIPERIDIN-1-YL)(CYCLOPROPYL)METHANONE

To a solution of3-(3-phenyl-1,2,4-oxadiazol-5-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine(60 mg, 0.15 mmol) in 1 mL of pyridine was added cyclopropanecarbonylchloride (28 μL, 0.30 mmol). The resulting mixture was stirred atambient temperature for 2 hours, followed by the addition of 20 mL ofwater to yield yellow precipitates. The precipitates were collected byfiltration, washed with water and purified by column chromatographyeluted with 5% methanol in dichloromethane to afford the title compoundas a yellow solid in 66% yield (45 mg). ¹H NMR (400 MHz, CDCl₃): δ 8.46(d, J=2.4 Hz, 1H), 8.33 (d, J=2.4 Hz, 1H), 8.18-8.13 (m, 2H), 7.79 (s,1H), 7.70 (s, 1H), 7.57-7.50 (m, 3H), 6.69 (br s, 2H), 4.85-4.73 (m,1H), 4.48-4.35 (m, 2H), 3.39-3.25 (m, 1H), 2.90-2.76 (m, 1H), 2.38-2.20(m, 2H), 2.15-1.95 (m, 2H), 1.84-1.76 (m, 1H), 1.05-0.98 (m, 2H),0.84-0.78 (m, 2H); MS (ES+): m/z 456.5 (M+1).

Example 7.1 SYNTHESIS OF(4-(4-(6-AMINO-5-(5-(2,6-DICHLOROPHENYL)-1,3,4-OXADIAZOL-2-YL)PYRIDIN-3-YL)-1H-PYRAZOL-1-YL)PIPERIDIN-1-YL)(CYCLOPROPYL)METHANONE

Following the procedure as described in Example 7, making variationsusing3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-pyridin-2-amineto replace3-(3-phenyl-1,2,4-oxadiazol-5-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amineto react with cyclopropanecarbonyl chloride, the title compound wasobtained as a yellowish solid in 41% yield. ¹H NMR (400 MHz, CDCl₃): δ8.40 (d, J=2.0 Hz, 1H), 8.14 (d, J=2.0 Hz, 1H), 7.74 (s, 1H), 7.65 (s,1H), 7.54-7.47 (m, 3H), 6.82 (br s, 2H), 4.82-4.69 (m, 1H), 4.46-4.32(m, 2H), 3.38-3.22 (m, 1H), 2.88-2.74 (m, 1H), 2.36-2.14 (m, 2H),2.10-1.90 (m, 2H), 1.82-1.74 (m, 1H), 1.04-0.96 (m, 2H), 0.82-0.75 (m,2H); MS (ES+): m/z 524.3, 525.3 and 526.3 (M+1).

Example 7.2 SYNTHESIS OF(4-(4-(6-AMINO-5-(5-(2,6-DICHLOROPHENYL)-1,3,4-OXADIAZOL-2-YL)PYRIDIN-3-YL)-1H-PYRAZOL-1-YL)PIPERIDIN-1-YL)(PHENYL)METHANONE

Following the procedure as described in Example 7, making variationsusing3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-pyridin-2-amineto replace3-(3-phenyl-1,2,4-oxadiazol-5-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amineto react with benzoyl chloride, the title compound was obtained as ayellowish solid in 83% yield. ¹H NMR (400 MHz, CDCl₃): δ 8.42 (s, 1H),8.12 (s, 1H), 7.75 (s, 1H), 7.67 (s, 1H), 7.53-7.49 (m, 3H), 7.46-7.39(m, 5H), 6.74 (br s, 2H), 4.95-4.75 (m, 1H), 4.47-4.37 (m, 1H),4.05-3.78 (m, 1H), 3.25-1.95 (m, 2H), 2.35-2.18 (m, 2H), 2.18-1.98 (m,2H); MS (ES+): m/z 560.3, 561.3 and 562.3 (M+1).

Example 8 SYNTHESIS OF5-(1-CYCLOHEXYL-1H-PYRAZOL-4-YL)-3-(5-PHENYL-1,2,4-OXADIAZOL-3-YL)PYRIDIN-2-AMINE

In a sealed tube, a mixture of5-bromo-3-(5-phenyl-1,2,4-oxadiazol-3-yl)pyridin-2-amine (70.0 mg, 0.221mmol),1-cyclohexyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(61.0 mg, 0.221 mmol) and cesium carbonate (145 mg, 0.442 mmol) in1,4-dioxane/water (2.0 mL, 4:1) was degassed with nitrogen gas for 10minutes, followed by the addition oftetrakis(triphenylphosphine)palladium (26.0 mg, 22.1 μmol). The mixturewas degassed for another 10 minutes. The resulting mixture was sealedand heated at 100° C. overnight. After cooled to ambient temperature,the reaction mixture was filtered through a celite cake, and washed withdichloromethane and methanol. The filtrate was concentrated and theresidue was treated with dichloromethane/methanol, and filtered. Thefiltrate was concentrated and the residue was purified by columnchromatography eluted with dichloromethane:methanol from 100:1 to 50:1to afford the title compound as a white solid in 41% yield (35 mg). ¹HNMR (400 MHz, CDCl₃): δ 8.52 (d, J=2.4 Hz, 1H), 8.40 (d, J=2.4 Hz, 1H),8.28-8.23 (m, 2H), 7.79 (s, 1H), 7.70 (s, 1H), 7.68-7.63 (m, 1H),7.62-7.56 (m, 2H), 6.25-6.10 (br s, 2H), 4.21-4.12 (m, 1H), 2.27-2.20(m, 2H), 2.00-1.90 (m, 2H), 1.85-1.74 (m, 3H), 1.54-1.40 (m, 2H),1.37-1.25 (m, 1H). MS (ES+): m/z 387.3 (M+1), 409.4 (M+Na).

Example 9 SYNTHESIS OF3-(5-(2,5-DICHLOROPHENYL)-1,2,4-OXADIAZOL-3-YL)-5-(1-(PIPERIDIN-4-YL)-1H-PYRAZOL-4-YL)PYRIDIN-2-AMINE

A. A mixture of5-bromo-3-(5-cyclohexyl-1,3,4-oxadiazol-2-yl)pyridin-2-amine (80 mg,0.208 mmol), tert-butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(94 mg, 0.249 mmol) and cesium carbonate (338 mg, 1.04 mmol) in a sealedtube with 5 mL of 10:1 dioxane:water was degassed with nitrogen for 10minutes, followed by the addition oftetrakis(triphenylphosphine)-palladium(0) (24 mg, 0.021 mmol). Themixture was degassed for another 10 minutes and then sealed and heatedat 110° C. overnight. After removal of the solvents, the residue waspurified by column chromatography and preparative thin layerchromatography eluted with 40% ethyl acetate in hexane to affordtert-butyl4-(4-(6-amino-5-(5-(2,5-dichlorophenyl)-1,2,4-oxadiazol-3-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylateas a yellowish solid in 30% yield (33 mg). ¹H NMR (400 MHz, CDCl₃): δ8.48 (d, J=2.4 Hz, 1H), 8.40 (d, J=2.4 Hz, 1H), 8.19 (d, J=2.4 Hz, 1H),7.80 (s, 1H), 7.69 (s, 1H), 7.57 (d, J=8.8 Hz, 1H), 7.53 (dd, J=8.8, 2.4Hz, 1H), 6.19 (br s, 2H), 4.38-4.20 (m, 1H), 3.30-3.27 (m, 2H),2.95-2.80 (m, 2H), 2.23-2.18 (m, 2H), 2.05-1.95 (m, 2H), 1.48 (s, 9H).

B. To a suspension of tert-butyl4-(4-(6-amino-5-(5-(2,5-dichlorophenyl)-1,2,4-oxadiazol-3-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(20 mg, 0.15 mmol) in 5 mL of dichloromethane was added 3 mL of 2M HClin ether. The resulting mixture was stirred at room temperatureovernight. After removal of the solvents in vacuo, the residue waspurified by preparative thin layer chromatography eluted with 1:10:89ammonium hydroxide:methanol:dichloromethane to afford the title compoundas a white solid in 68% yield (11 mg). ¹H NMR (400 MHz, CDCl₃): δ 8.49(d, J=2.4 Hz, 1H), 8.41 (d, J=2.4 Hz, 1H), 8.19 (d, J=2.4 Hz, 1H), 7.79(s, 1H), 7.71 (s, 1H), 7.57 (d, J=8.8 Hz, 1H), 7.52 (dd, J=8.8, 2.4 Hz,1H), 6.19 (br s, 2H), 4.28 (m, 1H), 3.30-3.27 (m, 2H), 2.85-2.75 (m,2H), 2.26-2.20 (m, 2H), 2.02-1.91 (m, 2H); MS (ES+): m/z 456.3 and 458.3(M+1).

Example 10 SYNTHESIS OF3-(5-PHENYL-1,2,4-OXADIAZOL-3-YL)-5-(1-(TETRAHYDRO-2H-PYRAN-4-YL)-1H-PYRAZOL-4-YL)PYRIDIN-2-AMINE

A mixture of 5-bromo-3-(5-phenyl-1,2,4-oxadiazol-3-yl)pyridin-2-amine(50 mg, 0.16 mmol),1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(55 mg, 0.20 mmol), and cesium carbonate (0.22 g, 0.82 mmol) in 3 mL of10:1 dioxane:water in a sealed tube was purged with nitrogen gas for 10minutes, followed by the addition oftetrakis(triphenylphosphine)-palladium(0) (10 mg, 0.008 mmol). Themixture was purged for another 10 minutes and heated at 110° C.overnight. After removal of the solvents, the residue was purified bycolumn chromatography and preparative thin layer chromatography elutedwith 2% methanol in dichloromethane to afford the title compound as awhite solid in 39% yield (25 mg). ¹H NMR (400 MHz, CDCl₃): δ 8.52 (d,J=2.4 Hz, 1H), 8.40 (d, J=2.0 Hz, 1H), 8.28-8.23 (m, 2H), 7.81 (s, 1H),7.72 (s, 1H), 7.68-7.63 (m, 1H), 7.62-7.56 (m, 2H), 6.20 (br s, 2H),4.47-4.37 (m, 1H), 4.20-4.10 (m, 2H), 3.63-3.54 (m, 2H), 2.23-2.10 (m,4H); MS (ES+): m/z 389.2 (M+1).

Example 11 SYNTHESIS OF3-(5-PHENYL-1,2,4-OXADIAZOL-3-YL)-5-(1-(PIPERIDIN-4-YL)-1H-PYRAZOL-4-YL)PYRIDIN-2-AMINE

A. A mixture of 5-bromo-3-(5-phenyl-1,2,4-oxadiazol-3-yl)pyridin-2-amine(100 mg, 0.33 mmol), tert-butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(0.15 mg, 0.40 mmol), and cesium carbonate (0.54 g, 1.65 mmol) in 5 mLof 10:1 dioxane:water in a sealed tube was purged with nitrogen gas for10 min, followed by the addition oftetrakis(triphenyl-phosphine)palladium(0) (19 mg, 0.05 mmol). Themixture was purged for another 10 minutes and then heated at 110° C.overnight. After removal of the solvents, the residue was purified bycolumn chromatography eluted with 2% methanol in dichloromethane toafford tert-butyl4-(4-(6-amino-5-(5-phenyl-1,2,4-oxadiazol-3-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylateas a yellowish solid in 63% yield (100 mg). ¹H NMR (400 MHz, CDCl₃): δ8.51 (d, J=2.4 Hz, 1H), 8.39 (d, J=2.4 Hz, 1H), 8.28-8.23 (m, 2H), 7.81(s, 1H), 7.70 (s, 1H), 7.68-7.63 (m, 1H), 7.62-7.57 (m, 2H), 6.19 (br s,2H), 4.47-4.20 (m, 3H), 3.00-2.85 (m, 2H), 2.24-2.10 (m, 2H), 2.05-1.92(m, 2H), 1.48 (s, 9H).

B. To a suspension of tert-butyl4-(4-(6-amino-5-(5-phenyl-1,2,4-oxadiazol-3-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(100 mg, 0.20 mmol) in 5 mL of dichloromethane was added 3 mL of 2M HClin ether. The resulting mixture was stirred at room temperature for 2hours, then diluted with 20 mL of dichloromethane, and washed withsaturated sodium bicarbonate solution. The organic solution wascollected and dried over anhydrous sodium sulfate. After filtration andremoval of the solvent in vacuo, the residue was purified by columnchromatography eluted with 1:10:89 ammoniumhydroxide:methanol:dichloromethane to afford the title compound as ayellow solid in 50% yield (40 mg). ¹H NMR (400 MHz, CDCl₃): δ 8.52 (d,J=2.4 Hz, 1H), 8.39 (d, J=2.4 Hz, 1H), 8.28-8.23 (m, 2H), 7.80 (s, 1H),7.72 (s, 1H), 7.68-7.63 (m, 1H), 7.62-7.57 (m, 2H), 6.19 (br s, 2H),4.33-4.24 (m, 1H), 3.33-3.24 (m, 2H), 2.86-2.76 (m, 2H), 2.26-2.18 (m,2H), 2.02-1.90 (m, 2H); MS (ES+): m/z 388.4 (M+1).

Example 12 SYNTHESIS OF1-(4-(4-(6-AMINO-5-(5-(2,6-DICHLOROPHENYL)-1,3,4-OXADIAZOL-2-YL)PYRIDIN-3-YL)-1H-PYRAZOL-1-YL)PIPERIDIN-1-YL)-2-PHENYLETHANONE

To a suspension of3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine(50 mg, 0.11 mmol) in 5 mL of dichloromethane at room temperature wasadded triethylamine (77 μL, 0.55 mmol), followed by the addition ofphenylacetyl chloride (18 μL, 0.13 mmol). The resulting mixture wasstirred at room temperature for 1 hour. After removal of the solvent invacuo, the residue was purified by column chromatography and preparativethin layer chromatography eluted with neat ethyl acetate to afford thetitle compound as a yellow solid in 34% yield (21 mg). ¹H NMR (400 MHz,CDCl₃): δ 8.40 (d, J=2.4 Hz, 1H), 8.10 (d, J=2.4 Hz, 1H), 7.72 (s, 1H),7.56 (s, 1H), 7.53-7.49 (m, 3H), 7.36-7.32 (m, 2H), 7.29-7.24 (m, 3H),6.64 (br s, 2H), 4.83-4.73 (m, 1H), 4.48-4.38 (m, 1H), 4.07-3.97 (m,1H), 3.78 (s, 2H), 3.22-3.11 (m, 1H), 2.86-2.75 (m, 1H), 2.25-2.15 (m,1H), 2.15-2.05 (m, 1H), 2.00-1.86 (m, 1H), 1.76-1.60 (m, 1H); MS (ES+):m/z 596.2, 597.2 and 598.2 (M+Na).

Example 12.1 SYNTHESIS OF(4-(4-(6-AMINO-5-(3-PHENYL-1,2,4-OXADIAZOL-5-YL)PYRIDIN-3-YL)-1H-PYRAZOL-1-YL)PIPERIDIN-1-YL)(PHENYL)METHANONE

Following the procedure as described in Example 12, making variationsusing3-(3-phenyl-1,2,4-oxadiazol-5-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amineto replace3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amineto react with benzoyl chloride, the title compound was obtained as apale yellowish solid in 45% yield. ¹H NMR (400 MHz, CDCl₃): δ 8.47 (d,J=2.4 Hz, 1H), 8.35 (d, J=2.4 Hz, 1H), 8.19-8.15 (m, 2H), 7.80 (s, 1H),7.71 (s, 1H), 7.57-7.53 (m, 3H), 7.47-7.43 (m, 5H), 6.68 (br s, 2H),4.98-4.82 (m, 1H), 4.50-4.41 (m, 1H), 4.10-3.95 (m, 1H), 3.25-3.00 (m,2H), 2.38-2.20 (m, 2H), 2.20-2.03 (m, 2H); MS (ES+): m/z 492.4 (M+1).

Example 12.2 SYNTHESIS OF1-(4-(4-(6-AMINO-5-(3-PHENYL-1,2,4-OXADIAZOL-5-YL)PYRIDIN-3-YL)-1H-PYRAZOL-1-YL)PIPERIDIN-1-YL)-2-PHENYLETHANONE

Following the procedure as described in Example 12, making variationsusing3-(3-phenyl-1,2,4-oxadiazol-5-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amineto replace3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amineto react with phenylacetyl chloride, the title compound was obtained asa pale yellowish solid in 49% yield. ¹H NMR (400 MHz, CDCl³): δ 8.43 (d,J=2.4 Hz, 1H), 8.31 (d, J=2.4 Hz, 1H), 8.19-8.13 (m, 2H), 7.75 (s, 1H),7.59 (s, 1H), 7.56-7.49 (m, 3H), 7.39-7.24 (m, 5H), 6.68 (br s, 2H),4.85-4.75 (m, 1H), 4.40-4.28 (m, 1H), 4.08-3.98 (m, 1H), 3.80 (s, 2H),3.25-3.12 (m, 1H), 2.88-2.78 (m, 1H), 2.28-2.17 (m, 1H), 2.17-2.06 (m,1H), 2.02-1.89 (m, 1H), 1.78-1.65 (m, 1H); MS (ES+): m/z 506.4 (M+1).

Example 13 SYNTHESIS OF3-(5-PHENYLOXAZOL-2-YL)-5-(1-(TETRAHYDRO-2H-PYRAN-4-YL)-1H-PYRAZOL-4-YL)PYRIDIN-2-AMINE

A mixture of 5-bromo-3-(5-phenyloxazol-2-yl)pyridin-2-amine (60 mg, 0.20mmol),1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(56 mg, 0.20 mmol) and cesium carbonate (0.32 g, 1.00 mmol) in a sealedtube with 5 mL of 10:1 dioxane:water was degassed for 10 min. After theaddition of tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol),the mixture was degassed for another 10 minutes. The resulting mixturewas sealed and heated at 100° C. overnight. After removal of the solventin vacuo, the residue was purified by column chromatography eluted withethyl acetate to afford the title compound as a yellow solid in 18%yield (14 mg). ¹H NMR (400 MHz, CDCl₃): (58.32 (d, J=2.4 Hz, 1H), 8.24(d, J=2.4 Hz, 1H), 7.79 (s, 1H), 7.77-7.72 (m, 2H), 7.69 (s, 1H),7.50-7.44 (m, 3H), 7.42-7.36 (m, 1H), 6.68 (br s, 2H), 4.50-4.38 (m,1H), 4.20-4.13 (m, 2H), 3.63-3.53 (m, 2H), 2.22-2.15 (m, 4H); MS (ES+):m/z 388.3 (M+1).

The table below shows additional examples of compounds of Formula (IA1)that were prepared according to the above process.

Ex. No. Chemical Name Starting Material and Yield Characterization Data13.1 tert-butyl 4-(4-(6- tert-butyl 4-(4-(4,4,5,5- ¹H NMR (400 MHz,CDCl₃): δ 8.30 amino-5-(5- tetramethyl-1,3,2- (d, J = 2.4 Hz, 1H), 8.22(d, J = 2.4 phenyloxazol-2- dioxaborolan-2-yl)-1H- Hz, 1H), 7.78 (s,1H), 7.75-7.71 (m, yl)pyridin-3-yl)- pyrazol-1-yl)piperidine-1- 2H),7.66 (s, 1H), 7.50-7.44 (m, 3H), 1H-pyrazol-1- carboxylate and5-bromo-3- 7.40-7.34 (m, 1H), 6.68 (br s, 2H), yl)piperidine-1-(5-phenyloxazol-2- 4.38-4.22 (m, 3H), 3.00-2.86 (m, 2H), carboxylateyl)pyridin-2-amine; 75% 2.24-2.14 (m, 2H), 2.06-1.92 (m, 2H), 1.47 (s,9H). 13.2 3-(5-(4- 5-bromo-3-(5-(4- ¹H NMR (400 MHz, DMSO-d₆): δchlorophenyl)oxazol- chlorophenyl)oxazol-2- 8.40 (d, J = 2.4 Hz, 1H),8.37 (d, J = 2-yl)-5-(1- yl)pyridin-2-amine and 1- 2.4 Hz, 1H), 8.28 (s,1H), 7.97-7.91 (tetrahydro-2H- (tetrahydro-2H-pyran-4-yl)- (m, 4H), 7.55(d, J = 8.4 Hz, 2H), 7.34 pyran-4-yl)-1H- 4-(4,4,5,5-tetramethyl- (br s,2H), 4.44-4.34 (m, 1H), 3.98- pyrazol-4- 1,3,2-dioxaborolan-2-yl)- 3.90(m, 2H), 3.50-3.41 (m, 2H), 2.04- yl)pyridin-2-amine 1H-pyrazole; 12%1.90 (m, 4H); MS (ES+): m/z 422.3 (M + 1). 13.3 tert-butyl 4-(4-(6-tert-butyl 4-(4-(4,4,5,5- ¹H NMR (400 MHz, CDCl₃): δ 8.31 amino-5-(5-(4-tetramethyl-1,3,2- (d, J = 2.4 Hz, 1H), 8.20 (d, J = 2.4chlorophenyl)oxazol- dioxaborolan-2-yl)-1H- Hz, 1H), 7.77 (s, 1H),7.68-7.64 (m, 2-yl)pyridin-3- pyrazol-1-yl)piperidine-1- 3H), 7.47-7.42(m, 3H), 6.68 (br s, yl)-1H-pyrazol-1- carboxylate and 5-bromo-3- 2H),4.38-4.22 (m, 3H), 3.00-2.84 (m, yl)piperidine-1-(5-(4-chlorophenyl)oxazol- 2H), 2.24-2.14 (m, 2H), 2.06-1.92 (m,carboxylate 2-yl)pyridin-2-amine; 90% 2H), 1.48 (s, 9H). 13.4 tert-butyl4-(4-(6- tert-butyl 4-(4-(4,4,5,5- ¹H NMR (400 MHz, CDCl₃): δ 8.40amino-5-(5-(4- tetramethyl-1,3,2- (d, J = 2.4 Hz, 1H), 8.22 (d, J = 2.4chlorophenyl)oxazol- dioxaborolan-2-yl)-1H- Hz, 1H), 7.79 (s, 1H),7.73-7.70 (m, 2-yl)pyridin-3- pyrazol-1-yl)piperidine-1- 1H), 7.68 (s,1H), 7.63-7.59 (m, 1H), yl)-1H-pyrazol-1- carboxylate and 5-bromo-3-7.49 (s, 1H), 7.44-7.38 (m, 1H), 7.36- yl)piperidine-1-(5-(3-chlorophenyl)oxazol- 7.32 (m, 1H), 6.68 (br s, 2H), 4.40-carboxylate 2-yl)pyridin-2-amine; 43% 4.25 (m, 3H), 3.00-2.87 (m, 2H),2.24- 2.16 (m, 2H), 2.06-1.94 (m, 2H), 1.49 (s, 9H). 13.5 3-(5-(3-1-cyclohexyl-4-(4,4,5,5- ¹H NMR (400 MHz, CDCl₃): δ 8.33chlorophenyl)oxazol- tetramethyl-1,3,2- (d, J = 2.0 Hz, 1H), 8.22 (d, J= 2.4 2-yl)-5-(1- dioxaborolan-2-yl)-1H- Hz, 1H), 7.77 (s, 1H),7.74-7.71 (m, cyclohexyl-1H- pyrazole and 5-bromo-3-(5- 1H), 7.68 (s,1H), 7.63-7.60 (m, 1H), pyrazol-4- (3-chlorophenyl)oxazol-2- 7.49 (s,1H), 7.43-7.39 (m, 1H), 7.36- yl)pyridin-2-amine yl)pyridin-2-amine; 19%7.33 (m, 1H), 6.66 (br s, 2H), 4.23- 4.13 (m, 1H), 2.28-2.20 (m, 2H),1.98-1.91 (m, 2H), 1.87-1.74 (m, 3H), 1.54-1.40 (m, 2H), 1.37-1.29 (m,1H); MS (ES+): m/z 420.3 and 422.3 (M + 1). 13.6 3-(5-(4-1-cyclohexyl-4-(4,4,5,5- ¹H NMR (400 MHz, CDCl₃): δ 8.34-Chlorophenyl)oxazol- tetramethyl-1,3,2- 8.30 (m, 1H), 8.22 (d, J = 2.4Hz, 1H), 2-yl)-5-(1- dioxaborolan-2-yl)-1H- 7.56 (s, 1H), 7.69-7.64 (m,3H), 7.47- cyclohexyl-1H- pyrazole and 5-bromo-3-(5- 7.43 (m, 3H), 6.65(s, 2H), 4.22-4.12 pyrazol-4- (4-chlorophenyl)oxazol-2- (m, 1H),2.26-2.19 (m, 2H), 1.99-1.80 yl)pyridine-2- yl)pyridin-2-amine; 4% (m,2H), 1.85-1.74 (m, 3H), 1.53-1.40 amine (m, 2H), 1.36-1.25 (m, 1H);(ES+): m/z 420.4, and 422.4 (M + 1). 13.7 5-(1-cyclohexyl-1-cyclohexyl-4-(4,4,5,5- ¹H NMR (400 MHz, CDCl₃): δ 8.321H-pyrazol-4-yl)- tetramethyl-1,3,2- (d, J = 2.4 Hz, 1H), 8.24 (d, J =2.4 3-(5-phenyloxazol- dioxaborolan-2-yl)-1H- Hz, 1H), 7.77-7.72 (m,3H), 7.66 (s, 2-yl)pyridin-2- pyrazole and 5-bromo-3-(5- 1H), 7.52-7.44(m, 3H), 7.41-7.35 (m, amine phenyloxazol-2-yl)pyridin- 1H), 6.64 (br s,2H), 4.22-4.10 (m, 2-amine; 24% 1H), 2.28-2.20 (m, 2H), 1.98-1.92 (m,2H), 1.86-1.73 (m, 3H), 1.53-1.40 (m, 2H), 1.36-1.25 (m, 1H); MS (ES+):m/z 386.4 (M + 1). 13.8 5-(1-cyclohexyl- 1-cyclohexyl-4-(4,4,5,5- ¹H NMR(400 MHz, CDCl₃): δ 8.31 1H-pyrazol-4-yl)- tetramethyl-1,3,2- (d, J =2.0 Hz, 1H), 7.89-7.84 (m, 3-(5- dioxaborolan-2-yl)-1H- 3H), 7.74 (s,1H), 7.65 (s, 1H), 7.55- phenylisoxazol-3- pyrazole and 5-bromo-3-(5-7.45 (m, 3H), 6.95 (s, 1H), 6.28-6.18 yl)pyridin-2-aminephenylisoxazol-3- (br s, 2H), 4.20-4.12 (m, 1H), 2.27-yl)pyridin-2-amine; 35% 2.18 (m, 2H), 1.98-1.90 (m, 2H), 1.84- 1.72 (m,3H), 1.53-1.40 (m, 2H), 1.36- 1.23 (m, 1H). MS (ES+): m/z 386.2 (M + 1).13.9 5-(1-(tetrahydro- 1-(tetrahydro-2H-pyran-4- ¹H NMR (400 MHz,CDCl₃): δ 8.31 2H-pyran-4-yl)- yl)-4-(4,4,5,5-tetramethyl- (d, J = 2.0Hz, 1H), 7.89-7.84 (m, 1H-pyrazol-4-yl)- 1,3,2-dioxaborolan-2-yl)- 3H),7.76 (s, 1H), 7.67 (s, 1H), 7.55- 3-(5- 1H-pyrazole and 5-bromo- 7.45(m, 3H), 6.95 (s, 1H), 6.38-6.28 phenylisoxazol-3-3-(5-phenylisoxazol-3- (br s, 2H), 4.45-4.35 (m, 1H), 4.18-yl)pyridin-2-amine yl)pyridin-2-amine; 24% 4.12 (m, 2H), 3.62-3.54 (m,2H), 2.21- 2.08 (m, 4H). MS (ES+): m/z 386.2 (M + 1). 13.10 tert-butyl4-(4-(6- tert-butyl 4-(4-(4,4,5,5- ¹H NMR (400 MHz, CDCl₃): δ 8.32amino-5-(5- tetramethyl-1,3,2- (d, J = 2.4 Hz, 1H), 7.90-7.85 (m,phenylisoxazol-3- dioxaborolan-2-yl)-1H- 3H), 7.75 (s, 1H), 7.66 (s,1H), 7.55- yl)pyridin-3-yl)- pyrazol-1-yl)piperidine-1- 7.48 (m, 3H),6.93 (s, 1H), 6.32-6.24 1H-pyrazol-1- carboxylate and 5-bromo-3- (br s,2H),), 4.37-4.16 (m, 3H), 3.00- yl)piperidine-1- (5-phenylisoxazol-3-2.82 (m, 2H), 2.22-2.10 (m, 2H), 2.10- carboxylate yl)pyridin-2-amine;44% 1.88 (m, 2H), 1.50 (s, 9H). 13.11 tert-butyl 4-(4-(6- tert-butyl4-(4-(4,4,5,5- ¹H NMR (400 MHz, CDCl₃): δ 8.20 amino-5-(5-tetramethyl-1,3,2- (d, J = 2.4 Hz, 1H), 7.86 (d, J = 2.4 phenylfuran-2-dioxaborolan-2-yl)-1H- Hz, 1H), 7.76-7.68 (m, 3H), 7.64 (s,yl)pyridin-3-yl)- pyrazol-1-yl)piperidine-1- 1H), 7.45-7.39 (m, 2H),7.33-7.28 (m, 1H-pyrazol-1- carboxylate and 5-bromo-3- 1H), 6.82-6.77(m, 2H), 5.22 (br s, yl)piperidine-1- (5-phenylfuran-2- 2H), 4.36-4.20(m, 3H), 2.95-2.70 (m, carboxylate yl)pyridin-2-amine; 64% 2H),2.22-2.15 (m, 2H), 2.05-1.92 (m, 2H), 1.48 (s, 9H). 13.125-(1-cyclohexyl- 1-cyclohexyl-4-(4,4,5,5- ¹H NMR (400 MHz, CDCl₃): δ8.20 1H-pyrazol-4-yl)- tetramethyl-1,3,2- (d, J = 2.4 Hz, 1H), 7.86 (d,J = 2.4 3-(5-phenylfuran- dioxaborolan-2-yl)-1H- Hz, 1H), 7.73 (s, 1H),7.72-7.68 (m, 2-yl)pyridin-2- pyrazole and 5-bromo-3-(5- 2H), 7.64 (s,1H), 7.45-7.40 (m, 2H), amine phenylfuran-2-yl)pyridin-2- 7.33-7.28 (m,1H), 6.80 (d, J = 3.6 amine; 24% Hz, 1H), 6.77 (d, J = 3.6 Hz, 1H), 5.23(br s, 2H), 4.20-4.10 (m, 1H), 2.26-2.18 (m, 2H), 1.97-1.89 (m, 2H),1.84-1.72 (m, 2H), 1.52-1.39 (m, 2H), 1.35-1.20 (m, 2H). MS (ES+): m/z385.3 (M + 1), 407.3 (M + Na). 13.13 5-(1-(tetrahydro5-bromo-3-(5-phenylfuran- ¹H NMR (400 MHz, CDCl₃): δ 8.202H-pyran-4-yl)- 2-yl)pyridin-2-amine and 1- (d, J = 2.4 Hz, 1H), 7.86(d, J = 2.4 1H-pyrazol-4-yl)- (tetrahydro-2H-pyran-4-yl)- Hz, 1H), 7.76(s, 1H), 7.74-7.71 (m, 3-(5-phenylfuran- 4-(4,4,5,5-tetramethyl- 1H),7.71-7.69 (m, 1H), 7.66 (s, 1H), 2-yl)pyridin-2-1,3,2-dioxaborolan-2-yl)- 7.45-7.40 (m, 2H), 7.33-7.28 (m, 1H), amine1H-pyrazole; 29% 6.80 (d, J = 3.6 Hz, 1H), 6.77 (d, J = 3.6 Hz, 1H),5.22 (br s, 2H), 4.44-4.35 (m, 1H), 4.18-4.10 (m, 2H), 3.61-3.53 (m,2H), 2.20-2.08 (m, 4H). MS (ES+): m/z 387.4 (M + 1). 13.14 tert-butyl4-(4-(6- 5-bromo-3-(5-(pyridin-3- ¹H NMR (400 MHz, CDCl₃): δ 9.04-amino-5-(5- yl)oxazol-2-yl)pyridin-2- 9.01 (m, 1H), 8.64-8.60 (m, 1H),8.34 (pyridin-3- amine and tert-butyl 4-(4- (d, J = 2.4 Hz, 1H), 8.24(d, J = 2.4 yl)oxazol-2- (4,4,5,5-tetramethyl-1,3,2- Hz, 1H), 8.05-7.99(m, 1H), 7.78 (s, yl)pyridin-3-yl)- dioxaborolan-2-yl)-1H- 1H), 7.68 (s,1H), 7.57 (s, 1H), 7.46- 1H-pyrazol-1- pyrazol-1-yl)piperidine-1- 7.40(m, 1H), 6.72 (br s, 2H), 4.40- yl)piperidine-1- carboxylate; 59% 4.20(m, 3H), 3.00-2.85 (m, 2H), 2.24- carboxylate 2.17 (m, 2H), 2.05-1.94(m, 2H), 1.49 (s, 9H).

Example 14 SYNTHESIS OF3-(5-PHENYLOXAZOL-2-YL)-5-(1-(PIPERIDIN-4-YL)-1H-PYRAZOL-4-YL)PYRIDIN-2-AMINE

To a solution of tert-butyl4-(4-(6-amino-5-(5-phenyloxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(60 mg, 0.12 mmol) in 4 mL of dichloromethane was added 1.0 mL of 2 Mhydrochloric acid in ethyl ether. The resulting mixture was stirred atambient temperature overnight, washed with saturated sodium bicarbonate(3×20 mL) and the organic layer was separated from the aqueous layer.The aqueous solution was extracted with dichloromethane (2×20 mL). Thecombined organic solution was dried over sodium sulfate and filtered.After removal of the solvent of the organic layer in vacuo, the residuewas purified by preparative thin layer chromatography eluted with1:10:89 ammonium hydroxide:methanol:dichloro-methane to afford the titlecompound as a yellow solid in 56% yield (26 mg). ¹H NMR (400 MHz,CD₃OD): δ 8.38 (d, J=2.4 Hz, 1H), 8.27 (d, J=2.4 Hz, 1H), 8.10 (s, 1H),7.86 (s, 1H), 7.85-7.80 (m, 2H), 7.63 (s, 1H), 7.49-7.43 (m, 2H),7.39-7.33 (m, 1H), 4.42-4.32 (m, 1H), 3.30-3.25 (m, 2H), 2.90-2.80 (m,2H), 2.22-2.14 (m, 2H), 2.10-1.95 (m, 2H); MS (ES+): m/z 387.4 (M+1).

The table below shows additional examples of compounds of Formula (IA1)that were prepared according to the above process.

Ex. No. Chemical Name Starting Material and Yield Characterization Data14.1 3-(5-(4- tert-butyl 4-(4-(6-amino- ¹H NMR (400 MHz, DMSO-d₆): δ8.40 (d, chlorophenyl)oxazol- 5-(5-(4- J = 2.0 Hz, 1H), 8.38 (d, J = 2.4Hz, 1H), 2-yl)-5- chlorophenyl)oxazol-2- 8.24 (s, 1H), 7.97-7.90 (m,4H), 7.58-7.54 (1-(piperidin-4- yl)pyridin-3-yl)-1H- (m, 2H), 7.34 (brs, 2H), 4.24-4.14 (m, 1H), yl)-1H-pyrazol- pyrazol-1-yl)piperidine-3.10-3.00 (m, 2H), 2.66-2.55 (m, 2H), 2.02- 4-yl)pyridin-2-1-carboxylate; 53% 1.93 (m, 2H), 1.88-1.74 (m, 2H); MS (ES+): amine m/z421.3 (M + 1). 14.2 3-(5-(3- tert-butyl 4-(4-(6-amino- ¹H NMR (400 MHz,DMSO-d₆): δ 9.32 (br chlorophenyl)oxazol- 5-(5-(3- s, 1H), 9.10 (br s,1H), 8.85 (d, J = 2.0 Hz, 2-yl)-5- chlorophenyl)oxazol-2- 1H), 8.54 (d,J = 2.0 Hz, 1H), 8.46 (s, 1H), (1-(piperidin-4- yl)pyridin-3-yl)-1H-8.14 (s, 1H), 8.13 (s, 1H), 8.11-8.09 (m, yl)-1H-pyrazol-pyrazol-1-yl)piperidine- 1H), 7.99-7.95 (m, 1H), 7.57-7.52 (m, 1H),4-yl)pyridin-2- 1-carboxylate; 98% 7.49-7.45 (m, 1H), 4.57-4.48 (m, 1H),3.42- amine 3.33 (m, 2H), 3.14-3.02 (m, 2H), 2.28-2.15 (m, 4H); MS(ES+): m/z 421.3 and 423.3 (M + 1). 14.3 3-(5- tert-butyl 4-(4-(6-amino-¹H NMR (400 MHz, CDCl₃): δ 8.32 (d, J = phenylisoxazol-5-(5-phenylisoxazol-3- 2.4 Hz, 1H), 7.90-7.85 (m, 3H), 7.75 (s,3-yl)-5-(1- yl)pyridin-3-yl)-1H- 1H), 7.67 (s, 1H), 7.55-7.47 (m, 3H),6.95 (piperidin-4-yl)- pyrazol-1-yl)piperidine- (s, 1H), 6.35-6.20 (brs, 2H), 4.32-4.23 (m, 1H-pyrazol-4- 1-carboxylate; 31% 1H), 3.31-3.24(m, 2H), 2.85-2.75 (m, 2H), yl)pyridin-2- 2.26-2.18 (m, 2H), 2.02-1.90(m, 2H). MS amine (ES+): m/z 387.4 (M + 1). 14.4 3-(5- tert-butyl4-(4-(6-amino- ¹H NMR (400 MHz, CD₃OD): δ 8.13 (d, J = phenylfuran-2-5-(5-phenylfuran-2- 2.4 Hz, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.72-yl)-5-(1- yl)pyridin-3-yl)-1H- 7.66 (m, 4H), 7.43-7.37 (m, 2H),7.31-7.25 (piperidin-4-yl)- pyrazol-1-yl)piperidine- (m, 1H), 6.78 (d, J= 3.6 Hz, 1H), 6.76 (d, J = 1H-pyrazol-4- 1-carboxylate; 65% 3.6 Hz,1H), 4.30-4.20 (m, 1H), 3.28-3.20 yl)pyridin-2- (m, 2H), 2.82-2.74 (m,2H), 2.23-2.15 (m, amine 2H), 2.00-1.88 (m, 2H). MS (ES+): m/z 386.4(M + 1). 14.5 5-(1-(piperidin- tert-butyl 4-(4-(6-amino- ¹H NMR (400MHz, DMSO-d₆): δ 9.41- 4-yl)-1H- 5-(5-(pyridin-3- 9.37 (m, 1H),9.27-9.18 (m, 1H), 9.10-8.98 pyrazol-4-yl)-3- yl)oxazol-2-yl)pyridin-3-(m, 1H), 8.95 (d, J = 2.4 Hz, 1H), 8.73-8.68 (5-(pyridin-3-yl)-1H-pyrazol-1- (m, 1H), 8.65-8.61 (m, 1H), 8.56 (d, J = yl)oxazol-2-yl)piperidine-1- 2.4 Hz, 1H), 8.49 (s, 1H), 8.26 (s, 1H), 8.15yl)pyridin-2- carboxylate; 69% (s, 1H), 7.79-7.73 (m, 1H), 4.57-4.48 (m,amine 1H), 3.43-3.33 (m, 2H), 3.14-3.02 (m, 2H), 2.28-2.12 (m, 4H); MS(ES+): m/z 388.2 (M + 1).

Example 15 SYNTHESIS OF1-(4-(4-(6-AMINO-5-(5-(4-CHLOROPHENYL)OXAZOL-2-YL)PYRIDIN-3-YL)-1H-PYRAZOL-1-YL)PIPERIDIN-1-YL)ETHANONE

To a solution of3-(5-(4-chlorophenyl)oxazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine(60 mg, 0.14 mmol) in 5 mL of dichloromethane at 0° C. was added aceticanhydride (13 μL, 0.14 mmol), followed by the addition of triethylamine(99 μL, 0.71 mmol). The resulting mixture was stirred at 0° C. for 30min, then warmed up to ambient temperature and stirred for 3 hours. Thesolvent was removed in vacuo, and the residue was purified by columnchromatography eluted with 5% methanol in dichloromethane followed byrecrystallization from methanol to afford the title compound as ayellowish solid in 51% yield (33 mg). ¹H NMR (400 MHz, DMSO-d₆): δ 8.40(d, J=2.4 Hz, 1H), 8.37 (d, J=2.4 Hz, 1H), 8.27 (s, 1H), 7.96-7.92 (m,4H), 7.57-7.54 (m, 2H), 7.34 (br s, 2H), 4.49-4.37 (m, 2H), 3.95-3.87(m, 1H), 3.25-3.16 (m, 1H), 2.75-2.67 (m, 1H), 2.12-2.03 (m, 2H), 2.02(s, 3H), 1.94-1.85 (m, 1H), 1.81-1.70 (m, 1H); MS (ES+): m/z 463.4 and465.4 (M+1).

Example 15.1 SYNTHESIS OF1-(4-(4-(6-AMINO-5-(5-(3-CHLOROPHENYL)OXAZOL-2-YL)PYRIDIN-3-YL)-1H-PYRAZOL-1-YL)PIPERIDIN-1-YL)ETHANONE

Following the procedure as described in Example 15, making variationsusing3-(5-(3-chlorophenyl)oxazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amineto replace3-(5-(4-chlorophenyl)oxazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amineto react with acetic anhydride, the title compound was obtained as ayellow solid in 65% yield. ¹H NMR (400 MHz, CDCl₃): δ 8.32 (d, J=2.4 Hz,1H), 8.22 (d, J=2.4 Hz, 1H), 7.80 (s, 1H), 7.74-7.71 (m, 1H), 7.69 (s,1H), 7.64-7.60 (m, 1H), 7.50 (s, 1H), 7.45-7.39 (m, 1H), 7.37-7.33 (m,1H), 6.70 (br s, 2H), 4.84-4.76 (m, 1H), 4.47-4.37 (m, 1H), 4.06-3.97(m, 1H), 3.32-3.22 (m, 1H), 2.85-2.76 (m, 1H), 2.35-2.20 (m, 2H), 2.17(s, 3H), 2.10-1.98 (m, 2H); MS (ES+): m/z 485.3 and 487.3 (M+Na).

Example 16 SYNTHESIS OF(4-(4-(6-AMINO-5-(5-(4-CHLOROPHENYL)OXAZOL-2-YL)PYRIDIN-3-YL)-1H-PYRAZOL-1-YL)PIPERIDIN-1-YL)(CYCLOPROPYL)METHANONE

To a solution of3-(5-(4-chlorophenyl)oxazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine(60 mg, 0.14 mmol) in 1 mL of pyridine was added cyclopropanecarbonylchloride (15 μL, 0.17 mmol). The resulting mixture was stirred atambient temperature for 2 hours. The solvent was removed in vacuo, andthe residue was purified by column chromatography eluted with 5%methanol in dichloromethane followed by recrystallization from a mixedsolvent of methanol and water to afford the title compound as an orangesolid in 63% yield (43 mg). ¹H NMR (400 MHz, CDCl₃): δ 8.31 (s, 1H),8.21 (s, 1H), 7.78 (s, 1H), 7.70-7.63 (m, 3H), 7.48-7.40 (m, 3H), 6.72(br s, 2H), 4.85-4.70 (m, 1H), 4.50-4.35 (m, 2H), 3.40-3.22 (m, 1H),2.91-2.75 (m, 1H), 2.40-2.20 (m, 2H), 2.15-1.90 (m, 2H), 1.85-1.75 (m,1H), 1.05-0.95 (m, 2H), 0.85-0.74 (m, 2H); MS (ES+): m/z 511.4 and 513.4(M+Na).

The table below shows additional examples of compounds of Formula (IA1)that were prepared according to the above process.

Ex. No. Chemical Name Starting Material and Yield Characterization Data16.1 (4-(4-(6-amino- 3-(5-(3- ¹H NMR (400 MHz, CDCl₃): δ 8.32 (d, J =5-(5-(3- chlorophenyl)oxazol-2- 2.4 Hz, 1H), 8.22 (d, J = 2.4 Hz, 1H),7.79 chlorophenyl)oxazol- yl)-5-(1-(piperidin-4- (s, 1H), 7.73-7.71 (m,1H), 7.68 (s, 1H), 2-yl)pyridin-3-yl)- yl)-1H-pyrazol-4- 7.63-7.59 (m,1H), 7.49 (s, 1H), 7.43-7.39 1H-pyrazol-1- yl)pyridin-2-amine and (m,1H), 7.36-7.32 (m, 1H), 6.67 (br s, 2H), yl)piperidin-1-cyclopropane-carbonyl 4.85-4.70 (m, 1H), 4.50-4.35 (m, 2H), 3.40-yl)(cyclopropyl) chloride; 36% 3.25 (m, 1H), 2.90-2.75 (m, 1H),2.37-2.17 methanone (m, 2H), 2.17-1.95 (m, 2H), 1.84-1.78 (m, 1H),1.05-0.98 (m, 2H), 0.82-0.76 (m, 2H); MS (ES+): m/z 489.3 and 491.3 (M +1). 16.2 (4-(4-(6-amino- 3-(5-(3- ¹H NMR (400 MHz, CDCl₃): δ 8.33 (d, J= 5-(5-(3- chlorophenyl)oxazol-2- 2.4 Hz, 1H), 8.22 (d, J = 2.4 Hz, 1H),7.80 chlorophenyl)oxazol- yl)-5-(1-(piperidin-4- (s, 1H), 7.74-7.72 (m,1H), 7.70 (s, 1H), 2-yl)pyridin-3-yl)- yl)-1H-pyrazol-4- 7.64-7.60 (m,1H), 7.50 (s, 1H), 7.48-7.44 1H-pyrazol-1- yl)pyridin-2-amine and (m,5H), 7.43-7.40 (m, 1H), 7.37-7.33 (m, yl)piperidin-1- benzoyl chloride;30% 1H), 6.69 (br s, 2H), 5.00-4.80 (m, 1H), yl)(phenyl)methanone4.50-4.41 (m, 1H), 4.08-3.93 (m, 1H), 3.25- 3.00 (m, 2H), 2.38-2.20 (m,2H), 2.20-2.00 (m, 2H); MS (ES+): m/z 525.3 and 527.3 (M + 1). 16.31-(4-(4-(6- 3-(5-(3- ¹H NMR (400 MHz, CDCl₃): δ 8.30 (d, J =amino-5-(5-(3- chlorophenyl)oxazol-2- 2.4 Hz, 1H), 8.20 (d, J = 2.4 Hz,1H), 7.77 chlorophenyl)oxazol- yl)-5-(1-(piperidin-4- (s, 1H), 7.73-7.71(m, 1H), 7.63-7.59 (m, 2-yl)pyridin-3-yl)- yl)-1H-pyrazol-4- 2H), 7.50(s, 1H), 7.46-7.39 (m, 1H), 7.38- 1H-pyrazol-1- yl)pyridin-2-amine and7.33 (m, 3H), 7.31-7.26 (m, 3H), 6.70 (br s, yl)piperidin-1-phenylacetyl chloride; 2H), 4.85-4.76 (m, 1H), 4.42-4.32 (m, 1H), yl)-2-37% 4.10-4.01 (m, 1H), 3.80 (s, 2H), 3.24-3.15 phenylethanone (m, 1H),2.88-2.78 (m, 1H), 2.37-2.20 (m, 1H), 2.18-2.08 (m, 1H), 2.05-1.92 (m,1H), 1.81-1.68 (m, 1H); MS (ES+): m/z 539.3 and 541.3 (M + 1). 16.4(4-(4-(6-amino- benzoyl chloride and 3- ¹H NMR (400 MHz, CDCl₃): δ 8.32(d, J = 5-(5-(4- (5-(4- 2.4 Hz, 1H), 8.21 (d, J = 2.4 Hz, 1H), 7.79chlorophenyl)oxazol- chlorophenyl)oxazol-2- (s, 1H), 7.69-7.65 (m, 3H),7.48-7.42 (m, 2-yl)pyridin-3-yl)- yl)-5-(1-(piperidin-4- 8H), 6.69 (brs, 2H), 4.95-4.80 (m, 1H), 1H-pyrazol-1- yl)-1H-pyrazol-4- 4.50-4.41 (m,1H), 4.08-3.93 (m, 1H), 3.25- yl)piperidin-1- yl)pyridin-2-amine; 3.00(m, 2H), 2.38-2.20 (m, 2H), 2.20-2.00 yl)(phenyl)methanone 54% (m, 2H);MS (ES+): m/z 525.3 and 527.3 (M + 1). 16.5 1-(4-(4-(6- phenylacetylchloride ¹H NMR (400 MHz, CDCl₃): δ 8.29 (d, J = amino-5-(5-(4- and3-(5-(4- 2.4 Hz, 1H), 8.19 (d, J = 2.4 Hz, 1H), 7.76chlorophenyl)oxazol- chlorophenyl)oxazol-2- (s, 1H), 7.69-7.64 (m, 2H),7.58 (s, 1H), 2-yl)pyridin-3-yl)- yl)-5-(1-(piperidin-4- 7.48-7.42 (m,3H), 7.38-7.32 (m, 2H), 7.31- 1H-pyrazol-1- yl)-1H-pyrazol-4- 7.25 (m,3H), 6.68 (br s, 2H), 4.85-4.76 (m, yl)piperidin-1- yl)pyridin-2-amine;1H), 4.41-4.32 (m, 1H), 4.10-4.01 (m, 1H), yl)-2- 36% 3.80 (s, 2H),3.24-3.13 (m, 1H), 2.89-2.78 phenylethanone (m, 1H), 2.28-2.19 (m, 1H),2.17-2.08 (m, 1H), 2.04-1.92 (m, 1H), 1.79-1.68 (m, 1H); MS (ES+): m/z539.3 and 541.3 (M + 1). 16.6 1-(4-(4-(6- pivaloyl chloride and 3- ¹HNMR (400 MHz, CDCl₃): δ 8.32 (d, J = amino-5-(5-(3- (5-(3- 2.4 Hz, 1H),8.22 (d, J = 2.4 Hz, 1H), 7.79 chlorophenyl)oxazol-chlorophenyl)oxazol-2- (s, 1H), 7.74-7.72 (m, 1H), 7.69 (s, 1H),2-yl)pyridin-3-yl)- yl)-5-(1-(piperidin-4- 7.64-7.60 (m, 1H), 7.50 (s,1H), 7.44-7.40 1H-pyrazol-1- yl)-1H-pyrazol-4- (m, 1H), 7.37-7.33 (m,1H), 6.67 (br s, 2H), yl)piperidin-1-yl)- yl)pyridin-2-amine; 4.65-4.55(m, 2H), 4.48-4.35 (m, 1H), 3.08- 2,2-dimethylpropan- 10% 2.95 (m, 2H),2.30-2.23 (m, 2H), 2.10-1.97 1-one (m, 2H), 1.33 (s, 9H); MS (ES+): m/z505.5 and 507.5 (M + 1). 16.7 (4-(4-(6-amino- 4-fluorobenzoyl ¹H NMR(400 MHz, CDCl₃): δ 8.32 (d, J = 5-(5-(3- chloride and 3-(5-(3- 2.4 Hz,1H), 8.22 (d, J = 2.4 Hz, 1H), 7.80 chlorophenyl)oxazol-chlorophenyl)oxazol-2- (s, 1H), 7.74-7.72 (m, 1H), 7.70 (s, 1H),2-yl)pyridin-3-yl)- yl)-5-(1-(piperidin-4- 7.64-7.60 (m, 1H), 7.51-7.46(m, 3H), 7.44- 1H-pyrazol-1- yl)-1H-pyrazol-4- 7.39 (m, 1H), 7.37-7.33(m, 1H), 7.16-7.09 yl)piperidin-1- yl)pyridin-2-amine; (m, 2H), 6.70 (brs, 2H), 4.48-4.35 (m, 2H), yl)(4-fluorophe- 12% 4.51-4.42 (m, 1H),3.22-3.04 (m, 2H), 2.34- nyl)methanone 2.20 (m, 2H), 2.19-2.05 (m, 2H);MS (ES+): m/z 543.3 and 545.3 (M + 1).

Example 17 SYNTHESIS OF3-(5-(3-CHLOROPHENYL)OXAZOL-2-YL)-5-(1-(1-METHYLPIPERIDIN-4-YL)-1H-PYRAZOL-4-YL)PYRIDIN-2-AMINE

To a solution of3-(5-(3-chlorophenyl)oxazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine(50 mg, 0.12 mmol) in 4 mL of dichloromethane and methanol (1:1) at 0°C. was added formaldehyde (10 μL, 0.14 mmol), followed by the additionof sodium cyanoborohydride (9 mg, 0.14 mmol). The resulting mixture waswarmed up to ambient temperature and stirred for another hour. Thesolvent was removed in vacuo and the residue was purified by columnchromatography eluted with 1:10:89 ammonium hydroxide:methanol:dichloromethane to afford the title compound as a yellow solid in 83%yield (43.2 mg). ¹H NMR (400 MHz, CDCl₃): δ 8.32 (d, J=2.4 Hz, 1H), 8.21(d, J=2.4 Hz, 1H), 7.78 (s, 1H), 7.73-7.68 (m, 2H), 7.63-7.58 (m, 1H),7.49 (s, 1H), 7.43-7.38 (m, 1H), 7.38-7.32 (m, 1H), 6.67 (br s, 2H),4.26-4.16 (m, 1H), 3.09-3.00 (m, 2H), 2.38 (s, 3H), 2.30-2.10 (m, 6H);MS (ES+): m/z 435.3 and 437.3 (M+1).

The table below shows additional examples of compounds of Formula (IA4)that were prepared according to the above process.

Ex. No. Chemical Name Starting Material and Yield Characterization Data17.1 3-(5-(4- 3-(5-(4- ¹H NMR (400 MHz, CDCl₃) δ 8.32 (d, J =Chlorophenyl)- chlorophenyl)oxazol-2- 2.4 Hz, 1H), 8.22 (d, J = 2.4 Hz,1H), 7.77 oxazol-2-yl)-5- yl)-5-(1-(piperidin-4-yl)- (s, 1H), 7.70-7.66(m, 3H), 7.48-7.44 (m, (1-(1- 1H-pyrazol-4-yl)pyridin- 3H), 6.63 (br s,2H), 4.24-4.15 (m, 1H), methylpiperidin- 2-amine and 3.06-2.99 (m, 2H),2.36 (s, 3H), 2.26-2.09 4-yl)-1H- formaldehyde; 75% (m, 6H); (ES+): m/z435.4 and 437.4 (M + pyrazol-4- 1). yl)pyridin-2- amine 17.2 5-(1-(1-3-(5-phenyloxazol-2-yl)- ¹H NMR (400 MHz, CDCl₃) δ 8.32 (d, J =ethylpiperidin-4- 5-(1-(piperidin-4-yl)-1H- 2.4 Hz, 1H), 8.23 (d, J =2.4 Hz, 1H), 7.78- yl)-1H-pyrazol- pyrazol-4-yl)pyridin-2- 7.73 (m, 3H),7.70 (s, 1H), 7.51-7.45 (m, 4-yl)-3-(5- amine and acetaldehyde; 3H),7.41-7.35 (m, 1H), 6.66 (br s, 2H), phenyloxazol-2- 13% 4.27-4.18 (m,1H), 3.17-3.10 (m, 2H), 2.50 yl)pyridin-2- (q, J = 7.2 Hz, 2H),2.30-2.23 (m, 2H), amine 2.18-2.08 (m, 4H), 1.15 (t, J = 7.2 Hz, 3H); MS(ES+): m/z 415.4 (M + 1). 17.3 5-(1-(1- 3-(5-phenyloxazol-2-yl)- ¹H NMR(400 MHz, CDCl₃) δ 8.31 (d, J = dodecylpiperidin-5-(1-(piperidin-4-yl)-1H- 2.4 Hz, 1H), 8.23 (d, J = 2.4 Hz, 1H), 7.77-4-yl)-1H- pyrazol-4-yl)pyridin-2- 7.72 (m, 3H), 7.69 (s, 1H), 7.51-7.45(m, pyrazol-4-yl)-3- amine and dodecyl 3H), 7.40-7.35 (m, 1H), 6.65 (brs, 2H), (5-phenyloxazol- aldehyde; 23% 4.25-4.15 (m, 1H), 3.13-3.06 (m,2H), 2.43- 2-yl)pyridin-2- 2.35 (m, 2H), 2.25-2.18 (m, 2H), 2.16-2.06amine (m, 4H), 1.57-1.47 (m, 2H), 1.35-1.24 (m, 18H), 0.89 (t, J = 6.8Hz, 3H); MS (ES+): m/z 555.5 (M + 1). 17.4 5-(1-(1-3-(5-phenylisoxazol-3- ¹H NMR (400 MHz, CDCl₃): δ 8.30 (d, J =methylpiperidin- yl)-5-(1-(piperidin-4-yl)- 2.4 Hz, 1H), 7.88-7.83 (m,3H), 7.74 (s, 4-yl)-1H- 1H-pyrazol-4-yl)pyridin- 1H), 7.66 (s, 1H),7.54-7.44 (m, 3H), 6.94 pyrazol-4-yl)-3- 2-amine and (s, 1H), 6.32-6.22(br s, 2H), 4.23-4.13 (m, (5-phenylisoxazol- formaldehyde; 61% 1H),3.07-2.98 (m, 2H), 2.37 (s, 3H), 2.28- 3-yl)pyridin-2- 2.06 (m, 6H); MS(ES+): m/z 401.4 (M + amine 1). 17.5 5-(1-(1- 3-(5-phenylfuran-2-yl)- ¹HNMR (400 MHz, CDCl₃): δ 8.21 (d, J = methylpiperidin-5-(1-(piperidin-4-yl)-1H- 2.0 Hz, 1H), 7.86 (d, J = 2.0 Hz, 1H), 7.76-4-yl)-1H- pyrazol-4-yl)pyridin-2- 7.70 (m, 3H), 7.66 (s, 1H), 7.46-7.41(m, pyrazol-4-yl)-3- amine and 2H), 7.33-7.29 (m, 1H), 6.81 (d, J = 3.6Hz, (5-phenylfuran- formaldehyde; 30% 1H), 6.77 (d, J = 3.6 Hz, 1H),5.20 (s, 2H), 2-yl)pyridin-2- 4.25-4.16 (m, 1H), 3.10-3.00 (m, 2H), 2.25amine (s, 3H), 2.32-2.10 (m, 6H); MS (ES+): m/z 400.4 (M + 1).

Biological Examples Example 18 Kinase Enzymatic Activity AssaysPreparation of Active Recombinant Kinase Proteins:

Recombinant human Tyro3 (455-end, the gene accession number NM_006293),human Axl (473-end, the gene accession number NM_021913) and human Mer(578-872, the gene accession number NM_006343) were independentlyexpressed by baculovirus in Sf9 insect cells using an N-terminal GSTtag. The recombinant proteins were stored at −70° C. in a mediumcontaining 50 mM Tris-HCl, pH 7.5, 150 mM NaCl, 10 mM glutathione, 0.1mM EDTA, 0.25 mM DTT, 0.1 mM PMSF and 25% glycerol. The recombinantproteins were aliquoted into smaller quantities after centrifugation toavoid repeated handling and multiple freeze/thaw cycles for the mostfavorable performance.

Preparation of Assay Reagents:

Kinase Assay Buffer: This buffer solution consisted of the followingcomponents: 25 mM MOPS, pH 7.2, 12.5 mM β-glycerol-phosphate, 25 mMMgCl₂, 5 mM EGTA, 2 mM EDTA and DTT 0.25 mM which was added prior touse.

Kinase Dilution Buffer: Kinase Assay Buffer was diluted at a 1:4 ratio(5× dilution) with distilled water.

[³³P]-ATP assay cocktail: In a designated radioactive working area, a250 μM [³³P]-ATP assay cocktail was prepared by the addition of thefollowing components: 150 μL of 10 mM ATP stock solution, 100 μL[³³P]-ATP (1 mci/100 μL), 5.75 mL of kinase assay buffer. This solutionwas stored in 1 mL aliquots at −20° C.

ATP stock solution (10 mM): The ATP stock solution was prepared bydissolving 55 mg of ATP in 10 mL of kinase assay buffer. It was storedin 200 μL aliquots at −20° C.

Active Kinase Stock Solution: The active recombinant kinase protein (0.1μg/μL) was diluted with Kinase Dilution Buffer and the activity wasassayed using a serial dilution method. The specific activity isexpressed in nmoL/min/mg.

Substrates: poly(4:1 glu:tyr) is the substrate used for each kinaseTyro3, Axl and Mer: The peptide substrate was dissolved in water to givethe final concentration of 1 mg/mL.

Test compound solution: Test compound was dissolved in DMSO to obtain a10 mM solution. The assay solution was prepared by adding 5 μL of thissolution to 955 μL of 10% DMSO/water to obtain the final concentrationof 50 μM.

Assay Procedure:

The enzymatic activity of all three kinases was determined as follows.Using a 96-well plate, the wells were divided into three categories:Blank wells, Background wells and Test wells. In Test wells, 5 μL of thetest compound solution and 5 μL of the substrate solution were added. InControl wells, 5 μL of 10% DMSO/water and 5 μL of the substrate solutionwere added. In Blank wells, 10 μL of 10% DMSO/water was added. To eachwell was added 10 μL of Active Kinase Stock Solution to make up thevolume in each well to 20 μL. All test samples, controls and blanks wererun in duplicate. The reaction was initiated by the addition of 5 μL of[³³P]-ATP assay cocktail, bringing the final volume up to 25 μL in everywell. The mixture was incubated at room temperature for 30 minutes. Thereaction was terminated by transferring 10 μL of the reaction mixtureinto a Millipore MultiScreen filter plate (cat. number MSPHN6B50). Thefilter plate was washed in a 1% phosphoric acid solution with constantgentle shaking for 15 minutes and this step was repeated once. After theplate was dried in air, scintillation fluid was added to each well andthe radioactivity in each well in CPM was counted by a Microbeta TriLux.The corrected CPM in each test well was determined by subtracting theaverage value of Blank well values. Percentage of inhibition of thekinase enzymatic activity by the test compound was determined using thefollowing formula:

${\% \mspace{14mu} {Inhibition}} = {\left( {1 - \frac{{Average}\mspace{14mu} {of}\mspace{14mu} {corrected}\mspace{14mu} {CPM}\mspace{14mu} {in}\mspace{14mu} {Test}\mspace{14mu} {wells}}{{Average}\mspace{14mu} {of}\mspace{14mu} {corrected}\mspace{14mu} {CPM}\mspace{14mu} {in}\mspace{14mu} {Control}\mspace{14mu} {wells}}} \right) \times 100}$

The IC₅₀ values were determined in a similar way following a serialdilution of the test compound. The percentage of inhibition at eachconcentration was calculated following the above formula. The IC₅₀ wasestimated from the curve of % Inhibition against Concentration in logunit using Prism 5, version 5.01.

The following table summarizes the inhibitory activity on Tyro3, Axl andMer of the compounds of the disclosure. “+” represents the IC₅₀ is >10μM; “++” represents the 1 μM<IC₅₀<10 μM; “+++” represents the 0.5μM<IC₅₀<1 μM and “++++” represents the IC₅₀<0.5 μM.

IC₅₀ (nM) Chemical Name Tyro3 Axl Mer tert-butyl4-(4-(6-amino-5-(5-phenyl-1,3,4-oxadiazol-2- ++ ++ ++yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate tert-butyl4-(4-(6-amino-5-(5-(4-(tert-butyl)phenyl)-1,3,4- ++ +++ ++++oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1- carboxylatetert-butyl 4-(4-(6-amino-5-(5-(2,6-dichlorophenyl)-1,3,4- ++ +++ NDoxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1- carboxylatetert-butyl 4-(4-(6-amino-5-(5-(4-fluorophenyl)-1,3,4- ++ ++ ++oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1- carboxylate3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1H- ++++ ++++ ++++pyrazol-4-yl)pyridin-2-amine3-(5-phenyl-1,3,4-oxadiazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin- ++++ +++++++ 2-amine 3-(5-(4-(tert-butyl)phenyl)-1,3,4-oxadiazol-2-yl)-5-(1H- +++ + pyrazol-4-yl)pyridin-2-amine3-(5-(2,5-difluorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1H- ++++ ++++ ++pyrazol-4-yl)pyridin-2-amine3-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1H-pyrazol-4- ++++ +++++++ yl)pyridin-2-amine5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(5-(2,6-dichlorophenyl)- + + +1,3,4-oxadiazol-2-yl)pyridin-2-amine3-(3-phenyl-1,2,4-oxadiazol-5-yl)-5-(1-(tetrahydro-2H-pyran- + + +4-yl)-1H-pyrazol-4-yl)pyridin-2-amine tert-butyl4-(4-(6-amino-5-(5-(pyridin-2-yl)-1,3,4-oxadiazol- ++ ++++ ++2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate tert-butyl4-(4-(6-amino-5-(5-(pyridin-3-yl)-1,3,4-oxadiazol- ++ +++ ++2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate tert-butyl4-(4-(6-amino-5-(5-(pyrazin-2-yl)-1,3,4-oxadiazol- ++ ++++ ++2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate tert-butyl4-(4-(6-amino-5-(5-(cyclopropylmethyl)-1,3,4- ++ ++++ +++oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1- carboxylatetert-butyl 4-(4-(6-amino-5-(5-benzyl-1,3,4-oxadiazol-2- ++ ++++ ++yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate tert-butyl4-(4-(6-amino-5-(5-(thiazol-2-yl)-1,3,4-oxadiazol-2- ++ +++ ++yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate tert-butyl4-(4-(6-amino-5-(5-(4-(trifluoromethyl)-thiazol-2- ++ ++++ +yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate3-(5-phenyl-1,2,4-oxadiazol-3-yl)-5-(1H-pyrazol-4-yl)pyridin- ++++ ++++++ 2-amine 3-(3-phenyl-1,2,4-oxadiazol-5-yl)-5-(1H-pyrazol-4-yl)pyridin-++ +++ ++ 2-amine 5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(3-phenyl-1,2,4- ++++ + oxadiazol-5-yl)pyridin-2-amine3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1- ++++ ++++ ++++(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine3-(5-phenyl-1,3,4-oxadiazol-2-yl)-5-(1-(tetrahydro-2H-pyran- ++++ ++++++++ 4-yl)-1H-pyrazol-4-yl)pyridin-2-amine5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(5-phenyl-1,3,4- ++ ++ +oxadiazol-2-yl)pyridin-2-amine3-(3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl)-5-(1- ++++ ++ ++(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(3-(2,6-dichlorophenyl)- ++++ ++ ++1,2,4-oxadiazol-5-yl)pyridin-2-amine3-(5-(2,6-dichloro-3-fluorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1- ++++ ++++++++ (piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine3-(5-phenyl-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H- ++++ ++++++++ pyrazol-4-yl)pyridin-2-amine3-(5-(4-(tert-butyl)phenyl)-1,3,4-oxadiazol-2-yl)-5-(1- ++++ ++++ ++++(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine3-(5-(2,5-difluorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1- ++++ ++++ ND(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1- ++++ ++++ ND(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine3-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4- ++++ ++++++++ yl)-1H-pyrazol-4-yl)pyridin-2-amine3-(3-phenyl-1,2,4-oxadiazol-5-yl)-5-(1-(piperidin-4-yl)-1H- ++++ ++++++++ pyrazol-4-yl)pyridin-2-amine3-(5-(cyclopropylmethyl)-1,3,4-oxadiazol-2-yl)-5-(1- ++++ ++++ ++++(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-(pyridin-2-yl)- ++++ ++++++++ 1,3,4-oxadiazol-2-yl)pyridin-2-amine5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-(pyridin-3-yl)- ++++ ++++++++ 1,3,4-oxadiazol-2-yl)pyridin-2-amine5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-(pyrazin-2-yl)- ++++ +++++++ 1,3,4-oxadiazol-2-yl)pyridin-2-amine3-(5-benzyl-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H- ++++ ++++++++ pyrazol-4-yl)pyridin-2-amine5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-(thiazol-2-yl)- ++++ ++++++++ 1,3,4-oxadiazol-2-yl)pyridin-2-amine5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-(4- ++++ ++++ ++++(trifluoromethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2- amine3-(5-cyclohexyl-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)- ++++ ++++++++ 1H-pyrazol-4-yl)pyridin-2-amine3-(3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl)-5-(1- ++++ ++++ ++++(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1- ++++ ++++ ++++(piperidin-4-yl)-1H-pyrrol-3-yl)pyridin-2-amine1-(4-(4-(6-amino-5-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol- ++++ ++++++++ 2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanone1-(4-(4-(6-amino-5-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin-3- ++++ ++++++++ yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanone3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(1- ++++ ++++ ++++methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-phenyl- ++++ +++++++ 1,2,4-oxadiazol-3-yl)pyridin-2-amine5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-(3-phenyl- ++++ ++++++++ 1,2,4-oxadiazol-5-yl)pyridin-2-amine3-(3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl)-5-(1-(1- ++++ ++++ ++++methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-(3-phenyl- ++++ ++++++++ 1,2,4-oxadiazol-5-yl)pyridin-2-amine3-(3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl)-5-(1-(1- ++++ ++ ++++dodecylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine3-(3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl)-5-(1-(1- ++++ ++++ ++++ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(1- ++++ ++++ ++++ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(1- +++ ++ ++dodecylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine1-(4-(4-(6-amino-5-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol- +++ ++++++++ 2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-4-methylpentan-1-one(4-(4-(6-amino-5-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin-3- ++ ++ ++yl)-1H-pyrazol-1-yl)piperidin-1-yl)(cyclopropyl)methanone(4-(4-(6-amino-5-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2- ++++ ++++ ++yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1- yl)(cyclopropyl)methanone(4-(4-(6-amino-5-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2- ++++ ++++++++ yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1- yl)(phenyl)methanone5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(5-phenyl-1,2,4- + + +oxadiazol-3-yl)pyridin-2-amine3-(5-(2,5-dichlorophenyl)-1,2,4-oxadiazol-3-yl)-5-(1- ++++ ++++ +++(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine3-(5-phenyl-1,2,4-oxadiazol-3-yl)-5-(1-(tetrahydro-2H-pyran- +++ ++++ ++4-yl)-1H-pyrazol-4-yl)pyridin-2-amine3-(5-phenyl-1,2,4-oxadiazol-3-yl)-5-(1-(piperidin-4-yl)-1H- ++++ ++++++++ pyrazol-4-yl)pyridin-2-amine1-(4-(4-(6-amino-5-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol- ++ ++ ++2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2- phenylethanone(4-(4-(6-amino-5-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin-3- ++ ++ ++yl)-1H-pyrazol-1-yl)piperidin-1-yl)(phenyl)methanone1-(4-(4-(6-amino-5-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin-3- ++ +++ ++yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-phenylethanone3-(5-phenyloxazol-2-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H- ++++ ++++ +pyrazol-4-yl)pyridin-2-amine tert-butyl4-(4-(6-amino-5-(5-phenyloxazol-2-yl)pyridin-3- +++ ++++ ++yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate3-(5-(4-chlorophenyl)oxazol-2-yl)-5-(1-(tetrahydro-2H-pyran- + + +4-yl)-1H-pyrazol-4-yl)pyridin-2-amine tert-butyl4-(4-(6-amino-5-(5-(4-chlorophenyl)oxazol-2- ++ +++ ++yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate3-(5-(3-chlorophenyl)oxazol-2-yl)-5-(1-cyclohexyl-1H- ++ ++ ++pyrazol-4-yl)pyridin-2-amine3-(5-(4-chlorophenyl)oxazol-2-yl)-5-(1-cyclohexyl-1H- + + +pyrazol-4-yl)pyridin-2-amine5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(5-phenyloxazol-2- ++ ++ +yl)pyridin-2-amine5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(5-phenylisoxazol-3- ++ ++ ++yl)pyridin-2-amine3-(5-phenylisoxazol-3-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)- ++++ ++++ ++1H-pyrazol-4-yl)pyridin-2-amine5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(5-phenylfuran-2- ++ ++ ++yl)pyridin-2-amine3-(5-phenylfuran-2-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H- ++ ++ ++pyrazol-4-yl)pyridin-2-amine3-(5-phenyloxazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4- ++++ ++++++++ yl)pyridin-2-amine3-(5-(4-chlorophenyl)oxazol-2-yl)-5-(1-(piperidin-4-yl)-1H- ++++ ++++++++ pyrazol-4-yl)pyridin-2-amine3-(5-(3-chlorophenyl)oxazol-2-yl)-5-(1-(piperidin-4-yl)-1H- ++++ ++++++++ pyrazol-4-yl)pyridin-2-amine3-(5-phenylisoxazol-3-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4- ++++ ++++++++ yl)pyridin-2-amine3-(5-phenylfuran-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4- ++++ ++++ +++yl)pyridin-2-amine5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-(pyridin-3- ++++ ++++ ++++yl)oxazol-2-yl)pyridin-2-amine1-(4-(4-(6-amino-5-(5-(4-chlorophenyl)oxazol-2-yl)pyridin-3- + + +yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanone1-(4-(4-(6-amino-5-(5-(3-chlorophenyl)oxazol-2-yl)pyridin-3- ++++ ++++++++ yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanone(4-(4-(6-amino-5-(5-(4-chlorophenyl)oxazol-2-yl)pyridin-3- ++++ ++++ +yl)-1H-pyrazol-1-yl)piperidin-1-yl)(cyclopropyl)methanone(4-(4-(6-amino-5-(5-(3-chlorophenyl)oxazol-2-yl)pyridin-3- +++ ++++ ++yl)-1H-pyrazol-1-yl)piperidin-1-yl)(cyclopropyl)methanone(4-(4-(6-amino-5-(5-(3-chlorophenyl)oxazol-2-yl)pyridin-3- ++++ ++++ ++yl)-1H-pyrazol-1-yl)piperidin-1-yl)(phenyl)methanone1-(4-(4-(6-amino-5-(5-(3-chlorophenyl)oxazol-2-yl)pyridin-3- ++++ ++++++ yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-phenylethanone(4-(4-(6-amino-5-(5-(4-chlorophenyl)oxazol-2-yl)pyridin-3- ++++ ++++ ++yl)-1H-pyrazol-1-yl)piperidin-1-yl)(phenyl)methanone1-(4-(4-(6-amino-5-(5-(4-chlorophenyl)oxazol-2-yl)pyridin-3- ++++ ++++++ yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-phenylethanone1-(4-(4-(6-amino-5-(5-(3-chlorophenyl)oxazol-2-yl)pyridin-3- ++++ ++++++ yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2,2-dimethylpropan-1-one(4-(4-(6-amino-5-(5-(3-chlorophenyl)oxazol-2-yl)pyridin-3- ++++ ++++ ++yl)-1H-pyrazol-1-yl)piperidin-1-yl)(4- fluorophenyl)methanone3-(5-(3-chlorophenyl)oxazol-2-yl)-5-(1-(1-methylpiperidin-4- ++++ ++++++++ yl)-1H-pyrazol-4-yl)pyridin-2-amine3-(5-(4-chlorophenyl)oxazol-2-yl)-5-(1-(1-methylpiperidin-4- ++++ ++++++++ yl)-1H-pyrazol-4-yl)pyridin-2-amine5-(1-(1-ethylpiperidm-4-yl)-1H-pyrazol-4-yl)-3-(5- ++++ ++++ ++++phenyloxazol-2-yl)pyridin-2-amine5-(1-(1-dodecylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-(5- ++++ ++++ +++phenyloxazol-2-yl)pyridin-2-amine5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-(5- ++++ ++++ ++++phenylisoxazol-3-yl)pyridin-2-amine5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-(5- ++++ ++++ ++phenylfuran-2-yl)pyridin-2-amine

Example 19 Cell Viability Assay

Cell lines and reagents: A549 cells were cultured in Dulbecco's ModifiedEagle Medium (DMEM, HyClone) containing 10% fetal bovine serum (FBS,Life technologies) and maintained in a humidified incubator at 37° C.with 5% CO₂.

Cell viability assay protocol: 5×10³ A549 cells in 180 μL, of DMEMcontaining 0.5% FBS were seeded in 96-well flat bottom plates (Costar)and incubated in a humidified incubator at 37° C. with 5% CO₂ for 24hours. The test compound (20 μL) in different concentrations after aserial dilution was added to the wells to a final volume of 200 μL perwell. The wells with zero compound concentration were used as theControl wells and the Test wells contained different concentrations ofthe test compound. To the Blank wells were added medium only. After 48hours incubation, 40 μL, of MTS (Promega) was added to each well and theplates were incubated for 10 minutes to 1 hour at 37° C. The cellviability was estimated by measurement of optical density at 490 nmusing a microplate spectrophotometer (Molecular Devices).

Example 20 Thymidine Incorporation Assay

1×10⁴ A549 cells in 180 μL of DMEM containing 0.5% FBS were seeded in a96-well white Isoplate (PerkinElmer) and incubated in a humidifiedincubator at 37° C. with 5% CO₂ for 24 hours. The test compound indifferent concentrations after a serial dilution was added to the wellsto a final volume of 200 μL per well. The wells with zero compoundconcentration were used as the Control wells and the wells containingdifferent concentrations of the test compound were used as the Testwells. To the Blank wells were added water only. After 24-hourincubation, each well was labeled with 1 μCi of [³H]thymidine (specificactivity, 26.8 Ci/mmol, PerkinElmer), and plates were again incubated at37° C. overnight. After incubation, 50 μL of cold trichloroacetic acidwas added into each well and the plates were incubated at 4° C. for 1-2hours. Plates were subsequently washed with distilled water 5 times andair-dried at room temperature. Scintillation liquid was added to eachwell and radioactivity in CPM was counted using a MicroBeta TriLux(PerkinElmer) counter. The corrected CPM in each well was determined bysubtracting the average value of the Blank well values. Percentage ofinhibition of the thymidine incorporation at tested concentrations bythe test compound was determined using the following formula:

${\% \mspace{14mu} {Inhibition}} = {\left( {1 - \frac{{Average}\mspace{14mu} {of}\mspace{14mu} {corrected}\mspace{14mu} {CPM}\mspace{14mu} {in}\mspace{14mu} {Test}\mspace{14mu} {wells}}{{Average}\mspace{14mu} {of}\mspace{14mu} {corrected}\mspace{14mu} {CPM}\mspace{14mu} {in}\mspace{14mu} {Control}\mspace{14mu} {wells}}} \right) \times 100}$

The IC₅₀ was then estimated from the curve of % Inhibition againstconcentration in log unit using Prism 5, version 5.01.

Example 21 Colony Formation Assay (Method #1)

A549 cells were treated with the test compound at differentconcentrations (5, 1 and 0.2 μM) in DMEM containing 0.5% FBS at 37° C.for 1 hour. After treatment, cells were seeded in the agar containingthe test compound at different concentrations as outlined above in6-well plates and the plates were incubated at 37° C. for 2 weeks. DMEMcontaining the various concentrations of the test compound was added onthe top of agar and changed every 2-3 days. The viable colonies werestained with crystal violet and counted. This example is to demonstratethe capability of test compounds to prevent the formation of colonies.

Example 22 Colony Formation Assay (Method #2)

17,500 A549 cells were seeded in agar in each well of 6-well plates andcultured in DMEM containing 10% FBS at 37° C. for six days and thecolonies were formed. The test compound dissolved in DMEM with differentconcentrations was added to the test wells of the plates and DMEM withno test compound or with diluted DMSO was added to the control wells.The plates were incubated at 37° C. for 18-20 days during which periodthe DMEM containing 10% FBS and the various concentrations of testcompounds was changed every 2 to 3 days. The viable colonies werestained with crystal violet and counted. This example is to demonstratethe capability of teat compounds to inhibit the colony growth after theyare established and/or to eliminate the established colonies.

Example 23 Western Blot Assay

5×10⁵ A549 cells were starved in DMEM contains no FBS in 6-well plateovernight, and treated with different concentrations of test compoundsin serum-free medium for 30 minutes at 37° C. Cells were subsequentlystimulated with or without Gas6 (400 ng/mL) for 30 min at 37° C. Totalproteins were extracted from the test compound treated cells usingice-cold RIPA buffer (50 mM Tris-HCl, pH 7.5, 150 mM NaCl, 1 mM EDTA, 1%(v/v) Triton-X 100, 0.1 (w/v) SDS) supplemented with protease inhibitorcocktail and phosphatase inhibitors. Protein concentrations weredetermined using Bradford assay. Twenty micrograms of total proteinswere fractionated on 10% SDS-PAGE gels and transferred ontonitrocellulose membrane (Bio-rad). Transfer efficiency and loading wereconfirmed by reversible staining of the membrane with Ponseau S solution(MP Biomedicals) following protein transfer. Membranes were blocked atambient temperature with 5% non-fat dry milk in Tris-buffered saline(TBS) containing 0.1% Tween-20 (TBST) for 1 hour and incubated withprimary antibodies against Axl, Tyro3, phospho-AKT (Ser⁴⁷³), total AKTor β-actin at 4° C. After overnight incubation, membranes were washedwith TBST and incubated with a secondary horseradish peroxidase(HRP)-labeled antibody (Jackson ImmunoResearch Laboratories, Inc.) for 1hour at ambient temperature. Membranes were washed in TBST followingincubation with secondary antibodies. Bound antibody complexes weredetected and visualized using Luminata Classico Western HRP Substrate(Millipore).

All of the U.S. patents, U.S. patent application publications, U.S.patent applications, foreign patents, foreign patent applications andnon-patent publications referred to in this specification and/or listedin the Application Data Sheet are incorporated herein by reference, intheir entirety.

From the foregoing it will be appreciated that, although specificembodiments of the disclosure have been described herein for purposes ofillustration, various modifications may be made without deviating fromthe spirit and scope of the disclosure. Accordingly, the disclosure isnot limited except as by the appended claims.

1. A compound of Formula (I):

wherein: W is

each A, A¹ and A² is the same or different and independently —N═, —CR⁵═,or —O—; L is a heteroaryl, heterocyclyl, —N(R⁶)—, —O—, —C(O)—, —C(O)O—,—S(O)_(t)— where t is 0, 1, or 2, —CON(R⁶)—, —N(R⁶)CO—, —SO₂N(R⁶)—, or—N(R⁶)CON(R⁶)—; provided that when L is heteroaryl, L is not pyridinyl,pyrazinyl or thienyl; R¹ is alkyl, cycloalkyl, cycloalkylalkyl,haloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl,or heteroarylalkyl; R² is hydrogen, heterocyclyl, heterocyclylalkyl,cycloalkyl, alkyl, aralkyl, cycloalkylalkyl, heteroaryl,heteroarylalkyl, or aryl; each R³ and R⁴ is the same or different andindependently selected from hydrogen, alkyl, aralkyl, alkenyl,aralkenyl, alkynyl, aralkynyl, cycloalkyl, cycloalkylalkyl, halo, orhaloalkyl; R⁵, at each occurrence, is hydrogen, alkyl, aralkyl,cycloalkyl, cycloalkylalkyl, halo, or haloalkyl; and R⁶ is hydrogen,alkyl, cycloalkyl, cycloalkylalkyl, or haloalkyl, a stereoisomer,enantiomer or tautomer thereof, an isotopically enriched derivativethereof, a pharmaceutically acceptable salt thereof, a pharmaceuticalcomposition thereof or a prodrug thereof.
 2. The compound of claim 1wherein L is heteroaryl.
 3. (canceled)
 4. The compound of claim 1wherein L is divalent pyrrozolyl moiety and the compound is representedby Formula (IA):


5. The compound of claim 4, represented claim represented by Formula(IA1):


6. The compound of claim 5 wherein R¹ is aryl, heteroaryl, cycloalkyl orheterocyclyl, and R² is aryl, heteroaryl, cycloalkyl or heterocyclyl.7.-10. (canceled)
 11. The compound of claim 6 wherein each of R³ and R⁴is hydrogen; is phenyl or substituted phenyl; and R² is 1-piperidin-4-ylor substituted 1-piperidin-4-yl.
 12. The compound of claim 11 being:tert-butyl-4-(4-(6-amino-5-(5-phenyloxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;3-(5-phenyloxazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;tert-butyl4-(4-(6-amino-5-(5-(4-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;3-(5-(4-chlorophenyl)oxazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;1-(4-(4-(6-amino-5-(5-(4-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanone;(4-(4-(6-amino-5-(5-(4-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(cyclopropyl)methanone;3-(5-(3-chlorophenyl)oxazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;1-(4-(4-(6-amino-5-(5-(3-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanone;3-(5-(3-chlorophenyl)oxazol-2-yl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;(4-(4-(6-amino-5-(5-(3-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(cyclopropyl)methanone;(4-(4-(6-amino-5-(5-(3-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(phenyl)methanone;1-(4-(4-(6-amino-5-(5-(3-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-phenylethanone;(4-(4-(6-amino-5-(5-(4-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(phenyl)methanone;1-(4-(4-(6-amino-5-(5-(4-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-phenylethanone;3-(5-(4-chlorophenyl)oxazol-2-yl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;1-(4-(4-(6-amino-5-(5-(3-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2,2-dimethylpropan-1-one;(4-(4-(6-amino-5-(5-(3-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(4-fluorophenyl)methanone;or5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-phenyloxazol-2-yl)pyridin-2-amine.13. The compound of claim 6 wherein each of R³ and R⁴ is hydrogen; isphenyl or substituted phenyl; and R² is tetrahydropyranyl.
 14. Thecompound of claim 13 being:3-(5-phenyloxazol-2-yl)-5-(1-(tetrahydro-2pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;or3-(5-(4-chlorophenyl)oxazol-2-yl)-5-(1-(tetrahydro-2pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine.15.-16. (canceled)
 17. The compound of claim 6, wherein each of R³ andR⁴ is hydrogen; R¹ is heteroaryl; and R² is heterocyclyl.
 18. Thecompound of claim 17 being5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-(pyridin-3-yl)oxazol-2-yl)pyridin-2-amine.19. The compound of claim 4, represented by Formula (IA2):


20. The compound of claim 19 wherein R¹ is aryl, heteroaryl, cycloalkylor heterocyclyl, and R² is aryl, heteroaryl, cycloalkyl or heterocyclyl.21. (canceled)
 22. The compounds of claim 20 wherein: each of R³ and R⁴is hydrogen; is phenyl or substituted phenyl; and R² is piperidinyl,substituted piperidinyl, tetrahydropyranyl or cyclohexyl.
 23. Thecompound of claim 22 being:5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(5-phenylisoxazol-3-yl)pyridin-2-amine;3-(5-phenylisoxazol-3-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;3-(5-phenylisoxazol-3-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;or5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-phenylisoxazol-3-yl)pyridin-2-amine.24. The compound of claim 4, represented by Formula (IA3):


25. The compound of claim 24 wherein R¹ is aryl, heteroaryl, cycloalkylor heterocyclyl, and R² aryl, heteroaryl, cycloalkyl or heterocyclyl.26. (canceled)
 27. The compound of claim 25, wherein each of R³ and R⁴is hydrogen; R¹ is phenyl or substituted phenyl; and R² is piperidinyl,substituted piperidinyl, tetrahydropyranyl or cyclohexyl.
 28. Thecompound of claim 27 being:3-(5-phenylfuran-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-phenylfuran-2-yl)pyridin-2-amine;5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(5-phenylfuran-2-yl)pyridin-2-amine;or3-(5-phenylfuran-2-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine.29. The compound of claim 1, represented by Formula (IA4):


30. The compound of claim 29, wherein R¹ is aryl, heteroaryl,cycloalkyl, heterocyclyl, aralkyl, or cycloalkylalkyl; and R² ishydrogen, aryl, heteroaryl, cycloalkyl or heterocyclyl. 31.-34.(canceled)
 35. The compound of claim 30 wherein: each of R³ and R⁴ ishydrogen; R¹ is phenyl or substituted phenyl; and R² is piperidinyl orsubstituted piperidinyl.
 36. The compound of claim 35 being: tert-butyl4-(4-(6-amino-5-(5-phenyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;3-(5-phenyl-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;3-(5-(2,6-dichloro-3-fluorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;3-(5-(4-(tert-butyl)phenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;tert-butyl4-(4-(6-amino-5-(5-(4-(tert-butyl)phenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;3-(5-(2,5-difluorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;tert-butyl4-(4-(6-amino-5-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;3-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;tert-butyl4-(4-(6-amino-5-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;1-(4-(4-(6-amino-5-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanone;3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;1-(4-(4-(6-amino-5-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-4-methylpentan-1-one;(4-(4-(6-amino-5-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(cyclopropyl)methanone;(4-(4-(6-amino-5-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(phenyl)methanone;1-(4-(4-(6-amino-5-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-phenylethanone;3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;or3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(1-dodecylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine.37. The compound of claim 30 wherein: each of R³ and R⁴ is hydrogen; R¹is heteroaryl or substituted heteroaryl; and R² is piperidinyl orsubstituted piperidinyl.
 38. The compound of claim 37 being: tert-butyl4-(4-(6-amino-5-(5-(pyrazin-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;tert-butyl4-(4-(6-amino-5-(5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-(pyrazin-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine;5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine;tert-butyl4-(4-(6-amino-5-(5-(thiazol-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-(thiazol-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine;5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine;tert-butyl4-(4-(6-amino-5-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;tert-butyl4-(4-(6-amino-5-(5-(4-(trifluoromethyl)-thiazol-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;or5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-(4-(trifluoromethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine.39. The compound of claim 30 wherein: each of R³ and R⁴ is hydrogen; R¹is cycloalkylalkyl or aralkyl; and R² is piperidinyl or substitutedpiperidinyl.
 40. The compound of claim 39 being: tert-butyl4-(4-(6-amino-5-(5-(cyclopropylmethyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;3-(5-(cyclopropylmethyl)-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;tert-butyl4-(4-(6-amino-5-(5-benzyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;or3-(5-benzyl-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine.41. The compound of claim 30 wherein: each of R³ and R⁴ is hydrogen; R¹is phenyl or substituted phenyl; and R² is hydrogen, cycloalkyl ortetrahydropyranyl
 42. The compound of claim 41 being:3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine;3-(5-phenyl-1,3,4-oxadiazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine;3-(5-(4-(tert-butyl)phenyl)-1,3,4-oxadiazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine;3-(5-(2,5-difluorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine;3-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine;5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine;5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyridin-2-amine;3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;or3-(5-phenyl-1,3,4-oxadiazol-2-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine.43. The compound of claim 4, represented by Formula (IA5):


44. The compound of claim 43 wherein R¹ is aryl; and R² is heterocyclyl.45. (canceled)
 46. The compound of claim 44 wherein: each of R³ and R⁴is hydrogen; R¹ is phenyl or substituted phenyl; R² is piperidinyl orsubstituted piperidinyl.
 47. The compound of claim 46 being:3-(3-phenyl-1,2,4-oxadiazol-5-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;1-(4-(4-(6-amino-5-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanone;(4-(4-(6-amino-5-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(cyclopropyl)methanone;5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin-2-amine;(4-(4-(6-amino-5-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(phenyl)methanone;1-(4-(4-(6-amino-5-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-phenylethanone;3-(3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;3-(3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;3-(3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl)-5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin-2-amine;or3-(3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl)-5-(1-(1-dodecylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine.48. The compound of claim 44 wherein: each of R³ and R⁴ is hydrogen; R¹is phenyl or substituted phenyl; R² is hydrogen, tetrahydropyranyl orcyclohexyl.
 49. The compound of claim 48 being:5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin-2-amine;5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl)pyridin-2-amine;3-(3-phenyl-1,2,4-oxadiazol-5-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;3-(3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;or 3-(3-phenyl-1,2,4-oxadiazol-5-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine.50. The compound of claim 4, represented by Formula (IA6):


51. The compound of claim 50 wherein R¹ is aryl, R² is heterocyclyl. 52.(canceled)
 53. The compound of claim 51 wherein: each of R³ and R⁴ ishydrogen; R¹ is phenyl or substituted phenyl; and R² is hydrogen,piperidinyl, substituted piperidinyl, tetrahydropyranyl or cyclohexyl.54. The compound of claim 53 being:5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(5-phenyl-1,2,4-oxadiazol-3-yl)pyridin-2-amine;3-(5-phenyl-1,2,4-oxadiazol-3-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;3-(5-phenyl-1,2,4-oxadiazol-3-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-phenyl-1,2,4-oxadiazol-3-yl)pyridin-2-amine;3-(5-(2,5-dichlorophenyl)-1,2,4-oxadiazol-3-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;3-(5-phenyl-1,2,4-oxadiazol-3-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine.55.-63. (canceled)
 64. A pharmaceutical composition comprising acompound of claim 1 and a pharmaceutically acceptable excipient.
 65. Amethod of treating leukemia and lymphomas comprising administering to asubject in need thereof a pharmaceutically effective amount of thecompound of claim
 1. 66. (canceled)
 67. A method of treating restenosiscomprising administering to a subject in need thereof a pharmaceuticallyeffective amount of the compound of of claim
 1. 68. A method of treatingatherosclerosis/thrombosis comprising administering to a subject in needthereof a pharmaceutically effective amount of the compound of claim 1.69. A method of treating psoriasis comprising administering to a subjectin need thereof a pharmaceutically effective amount of the compound ofclaim
 1. 70.-72. (canceled)
 73. A method of treating rheumatoidarthritis comprising administering to a subject in need thereof apharmaceutically effective amount of the compound of claim
 1. 74. Amethod of treating osteoarthritis comprising administering to a subjectin need thereof a pharmaceutically effective amount of the compound ofclaim
 1. 75. A method of treating osteoporosis comprising administeringto a subject in need thereof a pharmaceutically effective amount of thecompound of claim
 1. 76. (canceled)
 77. A method of treatingmetastasized tumors comprising administering to a subject in needthereof a pharmaceutically effective amount of the compound of claim 1.78. A method of treating solid tumors comprising administering to asubject in need thereof a pharmaceutically effective amount of thecompound of claim 1.